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An Update of the Role of Renin Angiotensin in Cardiovascular Homeostasis

Farag, Ehab MD, FRCA*†,§; Maheshwari, Kamal MD*†; Morgan, Joseph MD; Sakr Esa, Wael Ali MD, PhD*; Doyle, D. John MD, PhD§

doi: 10.1213/ANE.0000000000000528
Cardiovascular Anesthesiology: Review Article
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The renin angiotensin system (RAS) is thought to be the body’s main vasoconstrictor system, with physiological effects mediated via the interaction of angiotensin II with angiotensin I receptors (the “classic” RAS model). However, since the discovery of the heptapeptide angiotensin 1–7 and the development of the concept of the “alternate” RAS system, with its ability to reduce arterial blood pressure, our understanding of this physiologic system has changed dramatically. In this review, we focus on the newly discovered functions of the RAS, particularly the potential clinical significance of these developments, especially in the realm of new pharmacologic interventions for treating cardiovascular disease.

From the Departments of *General Anesthesia and Outcomes Research, Cleveland Clinic, Cleveland, Ohio; Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; and §Cleveland Clinic Lerner College of Medicine of Case Western Reserve University/Department of General Anesthesia, Cleveland Clinic, Cleveland, Ohio.

Accepted for publication August 29, 2014.

Funding: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to D. John Doyle, MD, PhD, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University/Department of General Anesthesia, Cleveland Clinic, 9500 Euclid Ave./E-31, Cleveland, OH 44195., Address e-mail to doylej@ccf.org.

Since the 1898 discovery of renin,1 the renin angiotensin system (RAS) was thought to be the body’s main vasoconstrictor system, with physiologic effects mediated via the interaction of angiotensin (Ang) II with Ang 1 receptors (AT1 receptors) (Figs. 1 and 2). This model constitutes what is now known as the “classic” RAS model. With the discovery of the heptapeptide Ang (1–7) and elucidation of its physiologic role to reduce arterial blood pressure after microinjection into the nucleus tractus solitarii, the understanding of the RAS has changed dramatically. As a result, newer concepts of the RAS are now referred to as the “alternate” RAS. This review will focus on the newly discovered functions of the RAS and the alternate RAS2–4 as well as comment on their clinical significance, especially in the realm of new pharmacologic interventions for cardiovascular disease.

Figure 1

Figure 1

Figure 2

Figure 2

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BIOSYNTHESIS IN THE RAS AND THE ALTERNATE RAS

Ang II is generated by a 2-step proteolytic process from the precursor angiotensinogen. In the first step of this process, renin mediates the proteolytic conversion of angiotensinogen generated by the liver to the decapeptide Ang I. In the second step, Ang I is converted to the octapeptide Ang II by angiotensin-converting enzyme (ACE).5 In addition, Ang II can be synthesized intracellularly from angiotensinogen and renin. Moreover, high glucose can stimulate both smooth muscle cell chymase and cathepsin D to form intracellular Ang II from Ang I and angiotensinogen.6 Of note, cathepsin D is responsible for intracellular activation of prorenin to renin.7 Ang (1–7) can be generated from either Ang I or Ang II. For example, Ang (1–7) is produced from Ang I by neprilysin (also known as neutral endopeptidase 24.11), thimet oligopeptidase, or prolylendopeptidase through the removal of the last 3 amino acids of the Ang I precursor molecule. The ACE homolog, ACE2, is central to Ang (1–7) production. This monocarboxypeptidase removes the amino acid leucine from the C-terminus of Ang I to form the biologically active peptide Ang (1–9), which is subsequently cleaved to generate Ang (1–7) through ACE and neutral endopeptidase 24.11 hydrolysis.

The second method by which Ang (1–7) is produced is via Ang II. This occurs by the removal of the C-terminal phenylalanine from Ang II by ACE2 to form the heptapeptide. Of importance, ACE2 has 400 times greater affinity for Ang II than Ang I. Unlike ACE1, ACE2 does not metabolize bradykinin; however, it does hydrolyze the proinflammatory kinin, Des-Arg9-Bk. Consequently, ACE2 has vasodilation and anti-inflammatory effects.3,8–10 Ang II may also be generated from Ang I by chymase under some pathological conditions, for example, in the presence of vascular damage associated with atherosclerosis (Fig. 3). Chymase also activates matrix metalloproteinase 9 (MMP9) and, therefore, may be involved in the development of aneurysms.11 Chymase is a chymotrypsin-like serine protease that is stored in inactive complexes with heparin proteoglycan in secretory granules of mast cells at pH of 5.5. Since the optimum pH for chymase activity is between 7 and 9, the lower pH of the secretary granules helps contribute to its storage as an inactive form. Of note, the heparin proteoglycan complexed with chymase works to protect the chymase against the actions of endogenous protease inhibitors, prolonging the action of chymase in vascular tissue. This may explain why chymase inhibitors prevent neointimal lesion formation in canine experiments after vein grafting or arterial balloon dilation, whereas ACE inhibitors failed to prevent neointimal lesion formation.12,13 Interestingly, Ang II can be produced via the chymase pathway from Ang (1–12) in the human heart.14 The alternate chymase-dependent pathway predominates in the diabetic kidney. Thus, the use of ACE1s alone without AT1 receptor blockers (ARBs) does not completely prevent albuminuria in diabetic patients because Ang II can still be produced via the renal alternate chymase pathway and stimulate Ang II receptors.15,16

Figure 3

Figure 3

Ang III (angiotensin 2–8 heptapeptide) is produced from Ang II by aminopeptidase A. Ang III increases arterial blood pressure, vasopressin release, and thirst when experimentally administered in the central nervous system.17 In addition, it induces natriuresis via activation of Ang 2 receptors (AT2 receptors) in the proximal renal tubules.18 Ang IV (angiotensin 3–8 hexapeptide) is generated from Ang III by aminopeptidase M. Ang IV is an endogenous inhibitor for the insulin regulator aminopeptidase.1

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RAS AND ALTERNATE RAS RECEPTORS

Ang II mediates its effects through binding to G protein–coupled receptors (GPCRs): the AT1 and AT2 receptors. These receptors are regulated by GPCR-interacting proteins such as AT1 receptor–associated protein (ATRAP) and AT2 receptor–interacting protein (ATIP).19 Activation of the AT1 receptor stimulates phospholipase C, causing the hydrolysis of phosphatidylinositol 4,5-bisphosphate to form inositol 1,4,5-trisphosphate and diacylglycerol. Inositol 1,4,5-trisphosphate activation increases myoplasmic Ca++ concentrations and diacylglycerol signaling causes protein kinase C activation and vascular smooth muscle (VSM) contraction.20 In addition, activation of the AT1 receptor induces inhibition of 3',5'-cyclic adenosine monophosphate signaling, thus enhancing VSM cell contraction. Ang II activates the NADH/NADPH system, resulting in elevated levels of reactive oxygen species (ROS), including hydrogen peroxide (H2O2), hydroxyl radical (OH), and superoxide anion (O2). Elevated ROS reduces nitric oxide (NO) availability and NO-dependent dilation, thus enhancing the vasoconstrictor effect of AT1 receptor activation.21 Of note, the initial stimulation of AT1 creates a positive feedback loop in which O2 enhances protein kinase C activation and H2O2 activates both tyrosine kinase Src (Src) and epidermal growth factor, resulting in enhanced ROS production. Small changes in Ang II can result in a dramatic change in arterial blood pressure.20 The production of ROS by Ang II augments the inflammatory response by activating a nuclear factor-κB (NF-κB) transcription factor, enhancing cytokine transcript production.22,23 Ang II can also induce apoptosis through the ROS-mediated inhibition of the antiapoptotic protein bcl-2.24 It is interesting to note that Ang II induces VSM hypertrophy by increasing intracellular H2O2.23

ATRAP has 3 transmembrane domains that interact with the intracellular C-terminal domain of the AT1 receptor. Activation of ATRAP leads to internalization of the AT1 receptor and its subsequent downregulation. Similarly, overexpression of ATRAP in transgenic mice decreases neointimal formation, inflammatory response, and ROS formation in injured arteries compared with the responses occurring in wild-type mice.25 In contrast to the ATRAP-mediated downregulation of the AT1 receptor, ARAP1 and GABA receptor–associated protein promote trafficking of the AT1 receptor to the plasma membrane and thus enhance its functions.26,27 The activation of peroxisome proliferator–activated receptor gamma (PPAR-γ) inhibits AT1 receptor action and stimulates the AT2 receptor.28 Therefore, ARBs such as telmisartan and irbesartan have a partial PPAR-γ agonistic effect. Correspondingly, telmisartan has neuroprotective effects against ischemic brain damage and cognitive dysfunction in a mouse model of Alzheimer disease via the synergistic effects of AT1 receptor blockade and PPAR-γ stimulation (Fig. 4).29,30

Figure 4

Figure 4

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AT2 Receptor Functions and Associated Proteins

The AT2 receptor is mainly stimulated by Ang (1–7), and it produces effects counterbalancing those from AT1 receptor stimulation. That is, activation of the AT2 receptor results in vasodilation, NO release, and inhibition of proliferation and growth. Of importance, upregulation of AT2 receptors may exert neuroprotection in the penumbra of ischemic brain tissue, which may explain the observation that in the LIFE study, administration of the ARB losartan offered superior stroke protection compared with atenolol.31,32 ATIP (also named MTUS1—mitochondrial tumor suppressor gene 1) interacts with the C-terminal tail of the AT2 receptor. The interaction of the AT2 receptor with ATIP results in reduction of superoxide anion production, the expression of proinflammatory cytokines, neointimal formation, and atherosclerosis.33 Further, the nonpeptide AT2 receptor agonist known as “compound 21” significantly improved systolic and diastolic ventricular function in a rat model of myocardial infarction.34 In addition, the interaction of the AT2 receptor with its associated proteins ATIP, ErbB3, and TIMP-3 could result in attenuated tumor growth, vascularization, and metastasis in different models of cancer.28,35

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The Mas Receptor

Mas is a proto-oncogene (a gene that causes normal cells to become cancerous when mutated) that encodes a 7-transmembrane-domain GPCR that was identified by Santos et al.36 as a specific Ang (1–7) receptor. The Mas receptor hetero-oligomerizes with the AT1 and thereby inhibits the actions of Ang II.37 Therefore, the interaction of Ang (1–7) with the Mas receptor mediates antiproliferative and antiarrhythmic effects, leads to vasodilation via bradykinin and NO release, and stimulates renal sodium excretion.10

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Prorenin and Renin Receptors

Renin is an aspartyl protease that consists of 2 homologous lobes, with the cleft between the lobes containing an active site consisting of 2 catalytic aspartic residues. Prorenin has an amino-terminal prosegment that folds over the cleft between these 2 lobes, preventing the activation of angiotensinogen. Prorenin is activated in the renal juxtaglomerular cells by enzymes such as proconvertase and cathepsin B.38 In the presence of low pH or cold, prorenin can be activated by unfolding from the interlobe cleft by nonproteolytic activation.38 The single receptor for both prorenin and renin [known as (P)RR] was identified in 2002 as a 350-amino acid protein with a single transmembrane domain.39 Binding of (P)RR to its ligands results in unfolding of prorenin, rendering it capable of contributing to local Ang II generation. In addition, renin and prorenin binding causes a rapid phosphorylation of the (P)RR on serine and tyrosine residues, triggering mitogen-activated protein kinase (MAPK) pathways.39,40 Consequently, stimulation of (P)RR can have the same harmful effects as AT1 receptor stimulation by Ang II. The antagonism of (P)RR by synthetic handle region peptide (HRP) (which is a part of the prosegment of prorenin) has been evaluated in a variety of organ pathologies. The administration of HRP reduced cardiac hypertrophy and fibrosis in hypertensive rats without reducing arterial blood pressure, and it also reduced diabetic glomerulosclerosis and proteinuria.41,42 HRP was beneficial in experimental models of ocular disease, where its administration reduced retinal neovascularization.41 In addition, HRP suppresses pathologic angiogenesis and the inflammatory processes in experimental retinopathy of prematurity (Fig. 5).43,44

Figure 5

Figure 5

The coding sequence of a 8.9-kDa fragment of the (P)RR, called M8-9, is identical to that of a vascular proton-translocating ATPase (V-ATPase), also known as ATP6AP2. In addition to its role in neurotransmitter uptake and storage, V-ATPase acidifies intracellular vesicular bodies such as endosomes and lysosomes and acidifies urine in the collecting ducts.38,40 The role of (P)RR/V-ATPase in neurotransmitter uptake and storage could explain its role in cognitive function. This hypothesis is supported by the fact that (P)RR mutations were found in patients with X-linked mental retardation and epilepsy.45

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Genetic Polymorphism of ACE1 and ACE2

Plasma ACE1 levels are genetically determined and vary significantly. The ACE gene is located on the long arm (q) of chromosome 17. There are 3 well-characterized polymorphisms of the ACE gene (A-240T, I/D, and A2350G). The insertion/deletion (I/D) polymorphism of the ACE I gene accounts for half of the variance of plasma enzyme levels.46 This polymorphism is based on insertion, or deletion, of a 287-bp sequence of DNA in intron 16 of the gene,47,48 producing 1 of 3 genotypes (DD, ID, and II).49

Multiple studies have established the relationship between ACE polymorphisms and diverse clinical diseases such as hypertension, coronary artery disease, diabetic nephropathy, and lung cancer because it might enhance the production of Ang II with all its adverse effects. There is a modest positive association between the ACE I/D polymorphic variant and coronary artery disease.50 There is no conclusive evidence, however, for a relationship between an association of ACE I/D polymorphism and hypertension induced by increased Ang II production.48 However, an exonic polymorphism G2350A (rs4343) in the sequence coding for the ACE has a significant influence on plasma ACE levels. The ACE 2350A allele is associated with variable risk for hypertension among various populations in Asia (a significantly reduced hypertension risk among the Arab Gulf and Pakistani populations but an increased risk among Han Chinese).51 A modest positive association between the D allele and atherosclerosis has been found, especially in the presence of other environmental and genetic cardiovascular risk factors.48 ACE I/D polymorphisms play a significant role in microvascular disorders and diabetes.41 The presence of the D allele of the ACE gene increases the risk of diabetic nephropathy.52 ACE polymorphisms may also be linked to lung cancer; ACE gene A-240T polymorphisms may be genetic markers for the development of lung cancer in individuals of Chinese descent.53

The ACE2 gene resides on the X chromosome. Patel et al.54 examined variants in the ACE2 gene (rs1978124, rs2074192, rs4240157, rs4646156, rs4646188) in 503 Caucasian subjects with type 2 diabetes. Genetic variation in ACE2 was associated with hypertension and reduced systolic function in men and hypertension and increased left ventricular mass in women.54

Genetic variation plays an important role in upper airway angioedema in patients chronically treated with RAS antagonists, resulting mainly from impaired bradykinin metabolism.55 When ACE is inhibited, bradykinin inactivation is highly dependent on aminopeptidase P (APP) enzyme activity.45 Therefore, the incidence of angioedema is higher with ACE1 (0.1%–0.68%) than with ARB (0.1%–0.4%) medications. Single-nucleotide polymorphism C-2399A, located in the enhancer region of the XPNPEP2 (membrane-bound gene for aminopeptidase P) promoter results in reducing bradykinin inactivation, is more prevalent in African-American men. African-American men have high incidence of single-nucleotide polymorphism C-2399A, located in the enhancer region of the XPNPEP2 (membrane-bound gene for aminopeptidase P) promoter which results in reducing bradykinin inactivation. Other risk factors for developing angioedema with the use of RAS antagonists are female sex, history of smoking, age >65, and history of ACE1-induced cough.56,57

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CARDIOVASCULAR ACTIONS OF THE RAS

Cardiovascular homeostasis results from the balance between the dual effects of the RAS. The harmful effects of the classic RAS on the cardiovascular system resulting in hypertension and increased inflammation are mediated by Ang II via the AT1 receptor, while the counter-regulatory axis of RAS, which acts mainly by Ang (1–7) and its receptors AT2 and Mas, produces vasodilation, and anti-inflammatory effects. The vasoconstrictor effects of Ang II on VSM occur through AT1 receptor activation.

Ang (1–7) has vasodilatory, antithrombotic, antiproliferative, and anti-inflammatory effects.8,58 Most of these actions are mediated via Mas receptors. Ang (1–7) triggers NO release by Akt phosphorylation inducing the activation of endothelial NO synthase (eNOS) and inhibits Ang II–mediated changes in ROS.8 The loss of ACE2 increases ACE/Ang II activity and thereby increases activation of NADPH oxidase and metalloproteinase enzymes promoting ROS generation and the resulting degradation of the extracellular matrix.59 However, oral administration of the ACE2 activator XNT, the Mas receptor agonist AVE099, or the administration of Ang (1–7) to diabetic rats resulted in reduced hyperglycemia, cardiac dysfunction, hypertrophy, and fibrosis compared to control animals.60–62 Moreover, XNT was shown to elicit an endothelial-dependent vasorelaxation response in rodents, which was mediated by Mas receptors.63

In the heart, ACE2 is located in the vascular endothelium, smooth muscle, and cardiomyocytes, whereas Mas receptors are located mainly in cardiomyocytes. Mice deficient in Mas and ACE2 show reduced cardiac contractile function, a smaller peak in intracellular Ca++ flux during depolarization, and slower Ca++ kinetics due to reduced expression of sarcoplasmic reticulum calcium ATPase2a (SERCA2a).64 Ang (1–7) modulates Ca++ handling by increasing NO and eNOS activity, leading to activation of SERCA2a pump that transports the calcium ions from the cytoplasm into the sarcoplasmic reticulum, thereby preventing the pathologic effects of Ca++ overload. In addition, Ang (1–7) prevents left ventricular remodeling and preserves cardiac function. Further, Ang (1–7) reduces interstitial fibrosis by reducing the levels of transforming growth factor beta (TGF-β) and increasing MMP2 and MMP9 levels. Ang (1–7) is also involved in the regulation of cardiac fibrosis via the regulation of genes coding for inflammatory cytokines, thus mitigating oxidative damage.8,61,65 Ang (1–7) inhibits the activity of the transcription factor NFAT (nuclear factor of activated T cells) by preventing its translocation to the nucleus where it normally increases the production of prohypertrophic transcripts when stimulated by Ang II. In addition, Ang (1–7) modulates the activity of glycogen synthase kinase 3β (GSK3β) by preventing its inhibition by Ang II. GSK3β phosphorylates NFAT in the nucleus and promotes its nuclear export. Thus, GSK3β is considered a potent inhibitor to NFAT.66,67

The alternate RAS may form the basis for future treatments to preserve myocardial function after myocardial infarction. In a rat model, it was shown that selectively decreasing the expression and activity of ACE2 after myocardial infarction was associated with myocardial dysfunction; these effects were prevented with the ACE inhibitor enalapril.68 In a recent study, an infusion of Ang (1–7) after myocardial infarction in rodents was able to inhibit cardiac hypertrophy and improve cardiac function by stimulating the cardiac progenitor cells, whereas cardiomyocyte-derived Ang (1–7) had no effect.69 In addition, the use of lentivirus-mediated overexpression of Ang (1–7) in a myocardial infarction model of rats was shown to prevent myocardial infarction–induced impairment, decreased myocardial wall thinning, and increased cardiac gene expression of both ACE2 and bradykinin B2 receptors. Furthermore, the overexpression of Ang (1–7) was associated with decreased expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).70 Of importance, the mineralocorticoid receptor blocker eplerenone reduces oxidative stress by decreasing NADPH oxidase activity, decreasing ACE activity, and increasing ACE2 activity, thereby increasing Ang (1–7) and decreasing the formation of Ang II. These results could explain the benefit of using mineralocorticoid receptor blocker in patients with congestive heart failure that was demonstrated in the RALES and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) studies.71–73

The ACE/Ang II axis has potent proatherosclerotic effects, increasing inflammation and stimulating the expression of monocyte chemoattractant protein-1, resulting in macrophage accumulation. The ACE2/Ang (1–7) axis, by contrast, has antiatherosclerotic effects; it decreases oxidative stress and inflammation and inhibits inflammatory cell infiltration.58 Ang (1–7) acting via the Mas receptor inhibits proliferation and migration of VSM cells. In addition, it works as a vasodilator and antithrombotic agent. Ang (1–7) produces these effects via different mechanisms, including the release of prostaglandins (such as prostaglandin I2 and E2), resulting in increased 3',5'-cyclic adenosine monophosphate levels and inhibition of both the cyclooxygenase and MAPK pathways.74,75 In addition, Ang (1–7) (via the Mas receptor) increases NO levels by reciprocal phosphorylation/dephosphorylation at serine 1177 threonine 495 of the eNOS enzyme, increasing its activity. Thus, the production of Ang (1–7) improves vascular endothelial function and acts as a vasodilator.2,61 These results have been shown to have potential clinical importance in a recent study in which ARBs olmesartan or valsartan given for 6 months were associated with reduced coronary plaque volume in patients with stable angina pectoris. The regression in coronary plaque volume is associated with reduced incidence of myocardial infarction and revascularization.76,77

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SHOULD RAS ANTAGONISTS BE CONTINUED OR DISCONTINUED PERIOPERATIVELY?

The continuation of RAS antagonists during the perioperative period is controversial. Patients receiving chronic ACE1 or ARB medications may develop hypotension during general anesthesia, especially in the first 30 minutes after induction. This hypotension is more common in patients who received ACE1/ARB <10 hours compared with those who stopped >10 hours before anesthesia induction.78 Hypotension can be refractory to traditional adrenergic drugs, but it may be responsive to vasopressin receptor agonists such as vasopressin or terlipressin.79,80 However, in a systemic review, no solid evidence was found to support either the withholding or continuation of RAS antagonists to avoid hypotension during general anesthesia.81 Furthermore, continuation of RAS antagonists in the early postoperative period was shown to reduce the incidence of postoperative atrial fibrillation after cardiac surgery. Although the data are not conclusive, in that study, the rate of postoperative atrial fibrillation was higher in the control group (33.3%) versus the RAS antagonists (12.2%).82Table 1 summarizes studies supporting a benefit of continuation of RAS antagonist perioperatively. Anesthesiologists should consider the potential benefits for continuing RAS antagonists before surgery and restarting them early in the postoperative period, especially in patients with heart failure. Of course, to avoid hypotension, careful consideration must be given to the patient’s volume status before the induction of anesthesia.83

Table 1

Table 1

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RAS AND THE KIDNEY

In the kidney, Ang (1–7) is generated from Ang I and Ang II via the actions of enzymes such as ACE2, neutral endopeptidase 24.11, thimet oligopeptidase, and prolyl oligopeptidase, which are located in brush border membranes or in the cytoplasm. However, ACE2 is considered the main source for Ang (1–7) in renal tissue.84,85 The alternate RAS plays very important roles in protecting and preserving renal function. Ang (1–7) exerts both antidiuretic and diuretic effects in the proximal tubule according to its concentration. Ang (1–7) at low concentrations (10−9 M) stimulates Na-ATPase activity via AT1 receptors; however, at higher concentrations (10–6 M) it inhibits the Na-ATPase activity via AT2 receptors.86,87 Furthermore, at higher concentration Ang (1–7) counteracts the stimulatory effect of Ang II on proximal tubule Na-ATPase activity, an effect mediated by the Mas receptor.88 Of note, Na-ATPase enzyme is involved in fine tuning and the fast regulation of sodium reabsorption in the renal cortex.89

Ang (1–7) also plays a crucial role in renal hemodynamic regulation (Fig. 6). Excessive RAS activation results in high intrarenal Ang II levels and subsequent systemic and glomerular capillary hypertension, which further can lead to endothelial injury and eventual kidney damage.90,91 Infusion of Ang (1–7) resulted in dilation of the preconstricted renal afferent arterioles in rabbits and enhanced renal blood flow in another rat study.92,93 In addition, Ang (1–7) attenuated the hypertensive effects and the excessive norepinephrine release after renal nerve stimulation caused by Ang II in a rat isolated kidney model.94 Ang (1–7) also increases renal atrial natriuretic peptide production, which reduces oxidative stress, as well as inflammatory, fibrotic, and proliferative effects of Ang II in the kidney.95 Ang (1–7) has been shown to be an important physiological regulator of intraglomerular pressure that opposes the harmful effects of excessive Ang II production.85

Figure 6

Figure 6

In addition to its effects on renal hemodynamics and tubular transport, Ang (1–7) may have an important role in kidney extracellular matrix protein synthesis. Ang (1–7) has dual actions, providing an inhibitory growth effect in proximal tubule (antagonizing the effects of Ang II and high glucose), whereas in mesangial cells, it appears to have stimulatory effect.96 In the proximal tubule, Ang (1–7) inhibits Ang II–induced phosphorylation of 3 MAPK: p 38, extracellular signal-related kinase (ERK1/2), and c-Jun N-terminal kinase (JNK). Furthermore, Ang (1–7) blocks hyperglycemia-induced transforming growth factor-β1 (TGF-β1), through binding to the Mas receptor; thereby, Ang (1–7) may partly counteract the profibrotic effects of hyperglycemia in the kidney.96,97 Interestingly, in the proximal tubule, Ang (1–7) exerts its protective effects against the synthesis of the extracellular protein matrix and cellular hypertrophy only in the presence of either hyperglycemia or RAS activation.4 In contrast to the growth-inhibiting effects of Ang (1–7) in the proximal tubule, Ang (1–7) stimulates growth-stimulatory pathways and DNA synthesis in mesangial cells, an effect mediated by the Mas receptor.

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The Role of ACE2/Ang (1–7)/Mas Axis in Renal Diseases

The vasodilation effect of Ang (1–7) may have therapeutic benefit in treating hypertension and in preventing hypertensive renal injury. Ang (1–7) stimulates NO production via a prostaglandin-dependent vasodilatory pathway, a response prevented by coadministration of indomethacin, a nonselective cyclooxygenase 1 and 2 inhibitor. Interestingly, the treatment with ACE1 and ARB is accompanied by elevated plasma levels of Ang (1–7), which may explain the mechanism of the therapeutic effects of these agents against the development of diabetic nephropathy and hypertension-induced kidney damage.98 In spontaneous hypertensive rats treated by chronic inhibition of NO synthesis with L-NAME, chronic administration of Ang (1–7) significantly reduced arterial blood pressure and proteinuria, and it was associated with a protective effect against hypertensive renal vascular injury. The infusion of indomethacin was able to prevent only the blood pressure–decreasing effect of Ang (1–7), but it did not reverse its protective effects on proteinuria, vascular reactivity, or renal vascular morphology.99 In addition, Ang (1–7) treatment reduced the renal expression of the proinflammatory cytokines IL-6, TNF-α, and NF-κB in stroke-prone spontaneous hypertensive rats. Finally, podocyte-specific overexpression of human ACE2 attenuates diabetic nephropathy in mice, as is evident by its nephrin protein preservation. Nephrin deficiency is associated with activation of NF-κB–mediated pathways that enhance glomerular injury.4,100,101

It is interesting that there are sex differences in renal ACE2 activity; rats had a 30% decrease in renal cortex expression of ACE2 protein after ovariectomy compared with controls. This effect was reversed by 17-beta-estradiol replacement.102 Therefore, estrogen-deficient females may be at increased risk of hypertensive renal injury, secondary to reduced levels of renal ACE2 and, consequently, Ang (1–7). Of further potential clinical importance, in the spontaneously hypertensive rats, the expression of ACE2 in the kidney was altered before the onset of hypertension.103 Specifically, the activity and expression of ACE2 increased in the kidney tubules of these animals before the onset of hypertension. However, over the course of renal development in spontaneously hypertensive rats, ACE2 expression does not significantly change compared to normotensive rats. Therefore, this finding supports the concept that ACE2 is downregulated in the kidneys of hypertensive rats.103 Consistent with these animal studies, a study of human renal biopsy specimens showed that the ratio of ACE to ACE2 was higher in subjects with hypertension compared with normotensive controls.104

Renal Ang III has been identified as a potential therapeutic target for treating hypertension. Ang II is metabolized into Ang III by aminopeptidase A and then degraded by aminopeptidase N. Ang III increases natriuresis by activating of AT2 receptors via a cyclic guanosine monophosphate–dependent mechanism. This natriuresis is enhanced by aminopeptidase-N inhibition. Therefore, aminopeptidase-N inhibition is an attractive therapeutic target in hypertension.18

The perioperative use of RAS antagonists may exert a protective effect against acute kidney injury (AKI). Intravenous enalapril at the induction of anesthesia in patients undergoing aortic surgery with infrarenal cross-clamping was associated with enhanced systemic oxygen delivery, improved splanchnic circulation, and improved glomerular filtration (GFR) rate 24 hours after surgery.105 In an observational study of 536 patients, the incidence of AKI after cardiac surgery was 6.4% in patients who received ACE1s before surgery and 12.2% in the control group, while the incidence of AKI requiring dialysis was 2.4% in the ACE1 group versus 6.3% in controls.106 However, the overall risk versus potential benefits of this strategy for reducing AKI has not been clearly established.

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DIABETIC NEPHROPATHY

Experimentally diabetes-associated high glucose concentration along with increased intracellular ROS generation induces Ang II formation in podocytes through upregulation of angiotensinogen expression.107 Ang II acts on AT1 receptors to further enhance ROS generation, MAPK activation, and TGF-β1 generation. Through these mechanisms, it enhances podocyte loss, glomerulosclerosis, and tubulointerstitial fibrosis.108 Therefore, RAS may accentuate pathologic changes in the kidney associated with diabetes. The administration of Ang (1–7) to streptozotocin-induced diabetic male rats reduced proteinuria and reduced vascular reactivity in isolated renal artery segments. In addition, treatment of streptozotocin-induced diabetic spontaneous hypertensive rats with Ang (1–7) reduced NAPDH oxidase activation, diminished proteinuria, and mitigated a hyperglycemia-induced increase in renal vascular responsiveness to endothelin-1, norepinephrine, and Ang II (Fig. 7).60,109 In a recent study, Nadarajah et al.101 showed that ACE2 overexpression in podocytes could delay and ameliorate the development of glomerulopathy in type I diabetes, indicating that ACE2 may slow the development of diabetic nephropathy via glomerular direct effects. Therefore, activation of the ACE2/Ang (1–7) axis is an attractive therapeutic intervention in diabetic nephropathy.100

Figure 7

Figure 7

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THE ROLE OF RAS IN LIVER FIBROSIS

The classic RAS and alternate RAS pathways play a crucial role in liver fibrosis, which is characterized by excessive deposition of extracellular matrix components. Liver fibrosis results from a complex pathological interaction between hepatic stellate cells, Kupffer cells, cytokines, chemokines, and growth factors.110 Hepatic stellate cells are also called lipid storage cells, lipocytes, or Ito’s cells. Hepatic stellate cells lie in the space of Disse, which is the subendothelial space between hepatocytes and sinusoidal endothelial cells.111 The main function of hepatic stellate cells is to metabolize vitamin A and produce cytokines, growth factors, and inflammatory mediators. In addition, hepatic stellate cells play a vital role in the regulation of portal pressure. Of note, hepatic stellate cells can transform into myofibroblasts in response to chronic liver injury and have the ability to contract scar tissue and fibrous septa.110 The major stimuli for hepatic stellate cells include growth factors such as TGF-β, cytokines, and ROS released from hepatocytes, Kupffer cells, and inflammatory cells after hepatic injury.112 These stimuli induce inflammasome expression (a multiprotein oligomer responsible for activation of inflammatory processes), resulting in phenotypic changes and activation of hepatic stellate cells to myofibroblasts. Activated hepatic stellate cells are stimulated to produce extracellular matrix proteins (with collagen type I and III as major components), MMPs, and their respective tissue inhibitor metalloproteinases.110–112 The ability of hepatic stellate cells to secrete both MMPs and their respective inhibitor metalloproteinases indicates that fibrosis may be conditionally reversible (Fig. 8).

Figure 8

Figure 8

After liver injury, activated hepatic stellate cells and the hepatic myofibroblasts express AT1 receptors and other components of the RAS.113 Ang II, via AT1 receptors, induces contraction and proliferation of hepatic stellate cells, increasing hepatic acinar fibrosis. It is interesting to note that Ang II induces a contractile response in hepatic stellate cells similar to the effect elicited by endothelin-1. This effect was attenuated in the presence of vasodilators such as NO and prostaglandins and completely blocked by preincubation with the ARB losartan.113–115 Ang II stimulates hepatic stellate cell activation via JNK/ERK transduction pathways resulting in secretion of proinflammatory cytokines and ROS. Ang II induces ROS generation by activated NADPH oxidase. Therefore, it is not surprising that mice lacking NADPH oxidase subunit p47pbox, a regulatory subunit of NADPH oxidase, had attenuated liver injury and fibrosis compared with wild-type mice.116,117 AT1 receptor–deficient mice were protected from fibrosis, whereas AT2 receptor–deficient mice had worse liver fibrosis.111 Ang (1–7) has a protective effect against liver fibrosis. In bile-duct–ligated rats, Ang (1–7) infusion reduced the degree of histologic fibrosis and the amount of tissue type I collagen, hydroxyproline content, and α-smooth muscle actin expression.111 Ang (1–7) mediates its effects via Mas receptors, as Mas receptor antagonism worsens experimental fibrosis.118

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ACE1s AND ARBs IN THE TREATMENT OF LIVER FIBROSIS

The use of the classic RAS-blocking drugs (either ACE1s or ARBs) is a potentially attractive method for treating liver fibrosis. The use of ACE1s not only prevents the degradation of Ang (1–7) but also enhances ACE2 upregulation in rats with hepatic fibrosis.119 The use of ACE1s and ARBs was successful in preventing fatty liver and improved fibrosis in obese Zucker rats with a reduction in the hepatic expression of the profibrotic TNF-α and TGF-β1.120,121 Of importance, the use of captopril or losartan showed protective effects in an ischemia-reperfusion liver injury rat model mainly by blunting the production of proinflammatory mediators TNF-α and intercellular adhesion molecule-1 (ICAM-1).122 Whereas TNF-α is an upstream regulator of proinflammatory cytokine release, ICAM-1 separately directs leukocyte binding to activated endothelium after the inflammatory response has initiated, indicating that the AT system influences several distinct “nodes” of the inflammasome network. Despite the protective effects of blocking classic RAS in animal models of hepatic fibrosis, however, the potential benefits of ARB/ACE1 on liver fibrosis were examined in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. This trial was a prospective, randomized, controlled 10-center trial that enrolled 1050 subjects with chronic hepatitis C and advanced hepatic fibrosis. The results of this trial did not find a reduction in liver fibrosis score among the ARB/ACE1 users.123 These conflicting results between animal and human study results could be attributed to an increased proportion of diabetics in the ARB/ACE1 treatment arm of the study because diabetes is a well-recognized predictor of hepatitis C progression.123 On the other hand, RAS blockade was associated with reduction of hepatic inflammation and fibrosis due to hepatitis C in post–liver transplant patients.124,125 In addition, the use of recombinant ACE2 attenuated experimental fibrosis in mice with cholestatic and toxic liver injury and thus could be a potential therapeutic agent in the future.126

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HEPATORENAL SYNDROME

Hepatorenal syndrome occurs in 40% of patients with cirrhosis associated with portal hypertension and ascites. There are 2 types of hepatorenal syndromes. Type I is a very aggressive variant characterized by rapidly progressive renal failure with doubling of initial serum creatinine to a level higher than 2.5 mg/dL or 220 μmol/L in <2 weeks of diagnosis. In type II hepatorenal syndrome, there is moderate renal failure with serum creatinine >1.5 mg/dL (133 μmol/L) with a slowly progressive course. It appears spontaneously in most cases. RAS activation in liver cirrhosis with increased circulating levels of Ang II results in afferent renal arterial vasoconstriction, with consequent renal hypoperfusion and a progressive decrease in GFR. Paneth cells located in the small intestinal crypts produce defensins, which are a host of defense peptides and are active against bacteria, fungi, and viruses in response to injury. The production of IL-17 A, a proinflammatory cytokine that plays a critical role in both innate and adaptive immunity, by Paneth cells in response to bacterial exposure enhances renal injury during coexisting hepatic injury.127 While their use may have beneficial effects in ameliorating hepatic fibrosis, ACE1/ARB drugs may be detrimental to renal function due to hypotension and reduction of GFR.127–130 However, the alternate RAS is a novel therapeutic option in hepatorenal syndrome because Ang (1–7) produces a vasodilatory effect on preconstricted rabbit afferent arterioles via Mas receptor actions and NO release.92

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RAS AND ALTERNATE RAS IN DIABETES

Diabetes affects >19 million adults in the United States alone and 150 million adults worldwide; by the year 2025, there will be >300 million people with diabetes.131 The average life expectancy of a man age 40 years with diabetes is reduced by approximately 11.6 years.131 Clearly, new approaches to treating this condition are a public health imperative. Ang II has a prominent role in diabetes and its complications, including hypertension, retinopathy, nephropathy, and other cardiovascular complications. Ang II, acting via the AT1 receptor, increases insulin resistance and reduces NO production by inhibiting insulin signaling via inositol 3-phosphatidyl kinase (PI3K).132 Normally, insulin increases NO production in the vascular endothelium, which is crucial to enhancing skeletal muscle blood flow and glucose availability.132 In states of hyperinsulinemia, which in turn induce insulin resistance, target cells (e.g., adipose, muscle, and liver cells) fail to respond to insulin. In insulin resistance, insulin activates serine/threonine kinases that phosphorylate insulin receptor substrate-1 and inhibits its function in NO production.132 Furthermore, insulin can act on the MAPK pathway to promote cellular growth, proinflammatory, and prothrombotic actions.132 Ang II, acting via the AT1 receptor, enhances the effect of insulin on the MAPK pathway and thus promotes cellular proliferation, inflammation, and thrombosis.133 Of importance, in obese individuals who manifest insulin resistance, the increased Ang II generated from adipose angiotensinogen134 shifts in insulin action from the PI3K pathway to the MAPK pathway, which could explain at least in part the proatherogenic effect of hyperinsulinemia in such individuals.133,135 Ang II stimulates NADPH oxidase, which increases ROS production in adipocytes. Increased oxidative stress in adipocytes further increases insulin resistance via a decrease in plasma adiponectin.136 Adiponectin is a plasma adipokine essential for modulating lipid metabolism, insulin sensitivity, and anti-inflammatory activity.137 Decreased adiponectin levels in blood serum are a common feature of obesity and insulin resistance.136,137 In addition, hyperactivity of the ACE/Ang II/AT1 receptor axis leads to β-cell dysfunction and inhibition of proinsulin biosynthesis.138 RAS blockade was shown to reduce the new onset of type 2 diabetes in hypertensive patients in the HOPE139 and LIFE studies.31 In contrast to the classic RAS, the alternate RAS ACE2/Ang (1–7)/Mas receptor axis has various functions protecting against the development of diabetes. Ang (1–7) has an antioxidative effect in adipocytes, and it enhances serum levels of adiponectin, helping to improve glucose uptake and decrease insulin resistance.136 Furthermore, Ang (1–7) enhances insulin action by activating the PI3K/AKT pathway. These actions are further evidenced by the observation that chronic administration of Ang (1–7) results in the normalization of insulin resistance in fructose-fed rats, a model of metabolic syndrome.140 It is interesting that β-cell expression of ACE2 is increased in the early stages of type 2 diabetes as a compensatory mechanism; however, this enhanced expression is decreased in the later stages of the disease.138 In obese db/db mice, ACE2 overexpression significantly improved glucose tolerance, enhanced β-cell function and insulin content, and prevented their apoptosis.138 Therefore, it has been suggested that the use of ACE2 gene therapy could be a novel therapeutic approach for type 2 diabetes.138 The protective functions of the ACE2/Ang (1–7)/Mas axis in diabetes also may protect against microvascular complications. Among a cohort of patients with poor glycemic control, those who remained free of microvascular complications had higher expression levels of ACE2/Mas mRNA when compared with those who had microvascular complications.141

Therefore, the activation of the ACE2/Ang (1–7)/Mas axis could confer protection against the development of microvascular complications in diabetic patients.141 In a recent meta-analysis, the use of ACE1s was found to be associated with reduced all-cause mortality and major cardiovascular mortality and/or events in patients with diabetes.142 However, ARBs had no benefits on these outcomes.142 Other RAS peptides also have important functions in glucose metabolism. Des-aspartate-angiotensin I improves glucose tolerance via the AT1 receptor.143 Ang IV, via its action on insulin regulator aminopeptidase, enhances insulin-stimulated tyrosine phosphorylation of insulin regulator aminopeptidase and either enhances the translocation or prolongs the presence of glucose transporter type 4 (GLUT4) at the cell membrane.143

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THE FUNCTIONS OF THE RAS AND ALTERNATE RAS IN THE BRAIN

The effects of RAS and alternate RAS on cardiovascular control result in part from their actions in the central nervous system. RAS activity has been identified in several areas responsible for central blood pressure control in the brain, including the paraventricular nucleus subfornical organ, rostral ventrolateral medulla, area posterma, and nucleus tractus solitarius.144 The rostral ventrolateral medulla is the major vasomotor sympathetic system center and is responsible for maintenance of vasomotor tone and blood pressure. Endogenous Ang II and Ang (1–7) increase the activity in the rostral ventrolateral medulla and therefore contribute to the maintenance of blood pressure and renal sympathetic activity (both of which are more enhanced in hypertensive rats).145 ACE2 is responsible for the metabolism of other peptides not directly related to RAS such as apelin, neurotensin, and dynorphin.146 Of importance, apelin expression is enhanced in the rostral ventrolateral medulla of hypertensive rats compared to controls.145,147 However, overexpression of ACE2 and consequently Ang (1–7) production in the paraventricular nucleus attenuated the Ang II–induced increase in blood pressure and production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in the paraventricular nucleus. Therefore, the ACE2/Ang (1–7)/Mas axis results in anti-inflammatory and antihypertensive effects in the paraventricular nucleus.148 Ang (1–7) modulates baroreflex control within the nucleus tractus solitarius, and bradycardia in old rats was associated with the loss of an Ang (1–7) effect in the nucleus tractus solitarius (Fig. 9).149 In addition to its central cardiovascular modulator effects, Ang (1–7) influences noncardiovascular functions in the brain such as learning, memory, and neuroprotection. Ang (1–7) via its action on Mas receptors enhances NO production through neuronal NOS (nNOS) activation in the brain, which is a crucial factor for object recognition memory and long-term enhancement in the hippocampus and amygdala.150,151 Knockout Mas receptor rats had a deficit in object recognition memory, confirming the importance of the Ang (1–7)/Mas axis in learning and memory.152 Ang (1–7) may have an important neuroprotective role against cerebral ischemic stroke. It decreased the production of both nNOS and eNOS and diminished the expression of inducible NOS (iNOS) in animal studies.153 It is noteworthy that the induction of iNOS produces toxic levels of NO, contributing to neuronal ischemic death.154 The anti-inflammatory effects of Ang (1–7) enhance its neuroprotective effects during cerebral ischemia.154 The antioxidative effect of the ACE2/Ang (1–7)/Mas axis helps to maintain the integrity of endothelial function in cerebral arteries.155 Further, ACE2 deficiency results in impaired endothelial function in cerebral arteries in adult mice, and it augmented endothelial dysfunction during aging.155 Those effects could explain the beneficial effects of both ARBs and ACE inhibitors in improving the cognitive functions in hypertensive patients independent of their decreases in blood pressure.156,157 It is interesting that the ACE2/Ang (1–7) axis has been detected in the glial cells of the human retina.158 Intravitreal injection with Ang (1–7) decreased intraocular pressure in rabbits.159 In addition, intraocular administration of ACE2 or Ang (1–7) genes in diabetic rats conferred protection against diabetic retinopathy.158

Figure 9

Figure 9

Ang IV, an active (3–8) fragment of Ang II, is widely distributed in the brain.160 Ang IV is an endogenous competitive inhibitor of the Ang 4 receptor (AT4), which is identical to the insulin regulator aminopeptidase. The insulin regulator aminopeptidase is a critical regulator of GLUT4 trafficking by promoting the localization of GLUT4 from endosomes to GLUT4-specialized vesicles. In the hippocampus, Ang IV facilitates the uptake of glucose in pyramidal neurons by maintaining GLUT4 levels at the cell membrane.160 This may partially explain why Ang IV has been shown to both facilitate and enhance learning and memory.161–163 Memory enhancements observed in mice after Ang IV administration may also be explained by the observation that Ang IV modulates acetylcholine levels in the hippocampus via an extrahippocampal mechanism.164 Rapid improvements in both memory performance and associative learning in mice given Ang IV were recently confirmed to be dependent on the Ang IV receptor.163 Insulin regulator aminopeptidase also functions as an aminopeptidase and has been demonstrated to cleave peptide hormones including vasopressin, oxytocin, somatostatin, and the NO-dependent vasodilator bradykinin.165 Insulin regulator aminopeptidase knockout mice had improvement in neurologic performance, reduction in ischemic infarct size, and increased compensatory cerebral blood flow after transient middle cerebral artery ligation compared with wild-type controls.166 Knockout insulin regulator aminopeptidase mice were less sensitive to the development of acute pentylenetetrazol-induced seizures.167

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THE RAS AND ALTERNATE RAS IN LUNG PATHOPHYSIOLOGY

The lung is one of the major sources for systemic Ang II. Since the ACE D/D genotype is associated with high levels of Ang II, increased ROS, inflammation, and fibrosis, it is not surprising that in patients with chronic obstructive pulmonary disease, the ACE D/D genotype was associated with a higher incidence of impaired peripheral tissue oxygenation and unfavorable pulmonary complications compared with individuals with ACE D/I or ACE I/I.23 Ang II is a bronchoconstrictor and it is implicated in the development of asthma.168 Ang II activates the AT1 receptor, resulting in contractions of human airway smooth muscle cells via the Rho/ROCK2 pathway, an effect that can be reversed with Ang (1–7).168 ACE2/Ang (1–7) has protective effects on pulmonary function. In a mouse model of pulmonary hypertension, the ACE2 gene transfer prevented the development of pulmonary hypertension induced by monocrotaline.169 Furthermore, ACE2 gene transfer in mice after 6 weeks of monocrotaline treatment resulted in reversal of elevation in right ventricular systolic pressure.169 ACE2 overexpression has vasodilator, antifibrotic, antiproliferative, and anti-inflammatory effects in pulmonary circulation.169 Of importance, ACE2 has been identified as a receptor for severe acute respiratory syndrome in in vitro cell lines.170 ACE2 binds to coronal virus spike proteins, the etiologic agent of this syndrome, resulting in the downregulation of ACE2 expression, possibly explaining the progression of the disease to acute respiratory distress syndrome.170 Furthermore, ACE2 knockout mice are resistant to severe respiratory syndrome coronvirus infection.171

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PREECLAMPSIA AND RAS

Preeclampsia is the second leading cause of maternal mortality in the United States, affecting 7% to 10% of all pregnancies and often resulting in stillbirth and neonatal morbidity and mortality.172 The RAS plays an important role in the development of preeclampsia. In preeclampsia, AT1 receptor autoantibodies are found, and they function as agonists of the AT1 receptor in the placenta.173 The chorionic villi of preeclamptic women was shown to have higher Ang II levels, modest decreases in Mas receptors, and normal Ang (1–7) levels when compared with the chorionic villi from women without preeclampsia.174 Therefore, the increased Ang II levels in preeclamptic chorionic villi may contribute to the pathophysiology of preeclampsia by decreasing the maternal–fetal exchange of vital oxygen and nutrients.174

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NEW THERAPEUTIC DEVELOPMENT

Targeting the ACE2/Ang (1–7)/Mas axis has potential as a treatment for several hematologic and oncologic disorders as reviewed elsewhere.175–182 Some of these potential benefits result from the antiangiogenesis actions of Ang (1–7) in inhibiting both vascular endothelium growth factor, thereby reducing blood vessel density and tumor cell proliferation.181 Moreover, Ang (1–7) inhibits cyclooxygenase II enzyme activity that plays an important role in tumor growth and metastasis.178 In a retrospective cohort study of >5000 Scottish individuals, the use of ACE1s was associated with significantly greater cancer-free survival and survival without fatal cancer than other antihypertensive drugs, especially with sex-specific cancers183 in women and for smoking-related cancers.184

The improved understanding of the RAS pathways has led to the development of novel therapeutic interventions targeting Ang (1–7) and/or Mas receptors, which has potential for the management of cardiovascular disease.184–186 Drugs currently under laboratory investigation include ACE2 activators. These drugs activate ACE2 and promote Ang (1–7) formation and have been found to exert pulmonary anti-inflammatory, antifibrotic, and vasodilatory effects.187 Xanthenone, for example, is a compound that enhances ACE2 activity and was found to reduce blood pressure, improve heart function, and decrease the risk for thrombus formation in a spontaneously hypertensive rat model.187 Another drug, diminazene aceturate, activates ACE2 and has shown promising results in reducing pulmonary hypertension.187,188 There are further encouraging preliminary results with recombinant ACE2. This protein may be given by IV infusion for the treatment of adult respiratory distress syndrome.189

Ang (1–7) analogs have potential for treatment for a variety of conditions. Initial studies of Ang (1–7) analogs were found to have an unfavorable pharmacokinetic profile, with a short plasma half-life and rapid degradation in the gastrointestinal tract. Several approaches have been investigated to overcome these limitations. Hydroxypropyl β-cyclodextrin (HPβCD)185/Ang (1–7) helps protect Ang (1–7) during passage through the gastrointestinal tract, while liposome encapsulated Ang (1–7) can provide similar protection.185 Active analogs such as cyclic Ang (1–7) are more stable and increase bioavailability.185 The Mas receptor is the site through which Ang (1–7) acts, making it a target site for drug development. Mas agonists such as AVE0991 and CGEN-856S are being studied in animal models for treating heart failure, left ventricular dysfunction, myocardial infarction, and hypertension.185Table 2 lists novel compounds under investigation as potential treatments for various diseases.

Table 2

Table 2

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CONCLUSIONS

New discoveries involving the classic and alternate RAS pathways, as well as new insights concerning the use of ACE1 and ARB medications, offer immense potential for treating a variety of conditions. These developments have further implications as a strategy to improve perioperative care and outcomes of critically ill patients.

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DISCLOSURES

Name: Ehab Farag, MD, FRCA.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Ehab Farag approved the final manuscript.

Name: Kamal Maheshwari, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Kamal Maheshwari approved the final manuscript.

Name: Joseph Morgan, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Joseph Morgan approved the final manuscript.

Name: Wael Ali Sakr Esa, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Wael Ali Sakr Esa approved the final manuscript.

Name: D. John Doyle, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: D. John Doyle approved the final manuscript.

This manuscript was handled by: Charles W. Hogue, Jr, MD.

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