Introduction: cardiometabolic pathophysiology
Cardiometabolic disease is becoming a commonly used concept as we recognize the strong interrelationship between diabetes and cardiovascular disease (CVD) 1. Indeed, type 2 diabetes mellitus (T2DM) often occurs in association with cardiovascular risk factors, for example, hypertension, dyslipidemia/hypercholesterolemia, smoking, and obesity which, in turn, are associated with atherosclerosis, ischemic heart disease, and ventricular dysfunction 2. The pathophysiology is increasing in prevalence, primarily because of the obesity pandemic, which considerably increases morbidity and mortality 3,4.
The search for novel therapeutics to tackle cardiometabolic disease is ongoing as current interventions are not entirely successful. Medical practice in CVD care involves platelet-inhibiting and cholesterol-lowering drugs and the cornerstone of T2DM treatment is glycemic control, regulated through, for example, insulin, metformin, thiazolidinediones, exercise, and diet. Importantly, the US Food and Drug Administration stipulates that all new diabetes drugs must be deemed cardiovascular safe 5. This is noteworthy as pharmacological therapy for T2DM has been associated with an increased risk of heart failure, although preclinical duration and the severity of the patient’s diabetes are contributing factors to the cardiovascular impact 6,7.
An ideal therapeutic approach would be to develop drugs targeting both CVD and metabolic disease. Several attempts are ongoing and may involve targeting endoplasmic reticulum (ER) stress or intracellular calcium regulation, as reviewed recently 5. Indeed, ER stress contributes toward atherosclerotic plaque formation 8,9, exaggerated adipose inflammation 10,11, and pancreatic β-cell death 12, and drives mitochondria dysfunction, insulin resistance, and dyslipidemia in hepatocytes 13–15. Similarly, intracellular calcium may trigger macrophage (MΦ) apoptosis, hepatic glucose production, and defective insulin signaling 5, and regulation through calmodulin-dependent protein kinase II has been investigated as an approach that may inhibit cardiometabolic disease 16. Finally, a lucrative therapeutic option may be to promote inflammatory resolution as chronic inflammation drives cardiometabolic pathophysiology 5,17–19. This review describes the role of inflammation in the progression of cardiometabolic disease and how triggering inflammatory resolution through specialized proresolving lipid mediators (SPMs), such as the lipoxins (LXs), may provide a novel and useful therapeutic approach.
Inflammation and cardiometabolic disease
The central role of inflammation in cardiometabolic pathophysiology is increasingly recognized 5,17–19. Indeed, systemic low-grade inflammation, possibly due to alterations in the gut microbiota and permeability, is a cardinal sign of metabolic disease 20,21. Obesity also inhibits the proliferation and differentiation of preadipocytes and triggers ER unfolded protein response (UPR) stress as a protective mechanism to restore normal function by halting protein translation and stimulating the production of molecular chaperones. However, prolonged UPR stress activates inflammatory pathways and eventually apoptosis and/or necrosis. Furthermore, adipose hypertrophy and resulting hypoxia, hepatic stress responses, and systemic hyperglycemia culminate in adipose inflammation and infiltration of inflammatory M1 MΦs 22,23. MΦ-derived proinflammatory mediators [tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6] are associated with the development of insulin resistance, and the subsequent release of free fatty acids causes systemic lipotoxicity, thus injuring pancreatic β-cells, the cardiovascular system, and indeed organs such as the liver and kidneys 17,22–25. In addition, obesity-induced inflammation disturbs the endocrine function of the adipose tissue, reducing the production of the protective hormone adiponectin, whereas leptin and resistin levels are increased, causing an adipokine imbalance that contributes to disease 17.
Similarly, inflammation plays a critical role in plaque formation and CVD 2,26,27 (Fig. 1). The atherosclerotic process may be initiated by irritants (e.g. hypertension, hyperlipidemia, or smoking) causing endothelial dysfunction. This results in LDL transmigrating through the vascular endothelium and accumulating in the arterial intima, where it is retained by binding to proteoglycans in the extracellular matrix. The rate of lipid accumulation is determined by LDL plasma concentration and the condition of the endothelium. LDL may be oxidized by superoxide released from endothelial cells and the activated endothelium upregulates adhesion molecules [intercellular adhesion molecule (ICAM); vascular cell adhesion molecule 1 (VCAM-1)], resulting in neutrophil recruitment. Neutrophils readily attempt to phagocytose the accumulated lipids and further oxidize LDL (oxLDL) by producing reactive oxygen species (ROS) and metalloproteinases (MMPs). oxLDL is considered a damage-associated molecular pattern molecule (DAMP) as it is recognized by pattern recognition receptors (PRRs), thus triggering a low-grade inflammatory response. The resulting production of proinflammatory cytokines and chemokines (RANTES, monocyte chemotactic protein, macrophage colony-stimulating factor) and increased expression of endothelial adhesion molecules amplify leukocyte recruitment and attract inflammatory monocytes. Monocytes migrate through the intima and differentiate into MΦs, which attempt to clear the inflammatory milieu by phagocytosing both lipid particles and apoptotic cells. MΦs may subsequently exit through the lymphatics or even egress from the plaque into the circulation 28–30, but a large number of cells remain trapped in the intima. The phagocytic ability of the MΦs is eventually exhausted and they transform into lipid-laden ‘foam cells’, which undergo necroptosis and form the necrotic lipid core of the plaque 31,32 (Fig. 1). Other leukocytes, including T-cells, B-cells, and natural killer (NK) cells, are also found in human atherosclerotic plaques 33. Indeed, Th1 cells may drive the M1 MΦ phenotype and foam cell formation, and CD8+ T-cells may promote plaque destabilization through expression of proinflammatory cytokines [TNF-α, interferon-γ (IFN-γ)] and cytotoxic molecules 26,34. Similarly, B-cells produce antibodies that opsonize oxLDL and promote MΦ-mediated phagocytosis. Furthermore, B-cells and neutrophil extracellular traps (NETs) activate dendritic cells (DCs), which, by secreting IL-12, amplify a proatherogenic Th1 response. NK T-cells also promote lesion formation through cytotoxic granzyme B and perforin expression. Regulatory T-cells (Treg) may, in contrast, serve as an anti-inflammatory mediator, inhibiting foam cell formation, and Treg promotes an antiatherogenic lipid profile in hypercholesterolemic mice 35.
As the inflammatory milieu drives plaque progression, endothelial cells and foam cells produce fibroblast growth factor and platelet-derived growth factor, which activate smooth muscle cells (SMCs) in the arterial wall, stimulating their proliferation and migration to the intima 2,36. SMCs produce collagens and elastin, which form a fibrous capsule that acts as a ‘barrier’ in advanced atheromata, and therefore, SMC apoptosis may cause detrimental cap thinning 37,38. Furthermore, SMCs may phagocytose lipids and become foam cells themselves 2. As the plaque continues to grow, an adaptive response occurs, whereby the adventia expands, in a process known as ‘remodeling’, which is a compensatory attempt to retain vascular function and leave the arterial lumen open. However, as the plaque buildup continues, the compensatory remodeling reaches its limit and the plaque protrudes into the lumen. Biodynamical and hemodynamic stresses may cause the plaque to rupture and if the necrotic core comes in contact with blood platelets, a thrombus forms and a cardiovascular event may occur. Interestingly, early plaques are more likely to rupture then stable, more advanced plaques protruding into the lumen 27. The plaques that are particularly vulnerable to rupture are localized at sites of turbulent flow and are characterized not necessarily by size per se, but rather by a soft lipid-rich necrotic core surrounded by an inflamed and thin fibrous capsule 39. Indeed, rupture may be a result of fibrous cap thinning because of defective collagen synthesis and/or MMP-mediated collagen degradation and/or insufficient inflammatory resolution 2,27.
Inflammation is an intricate and carefully regulated process that is required by the body to maintain health. In health, inflammation consists of two phases: an initial acute phase, followed by a resolving phase. The acute phase is initiated by peptides (cytokines, chemokines) and lipids (prostaglandins, leukotrienes), inducing edema and leukocyte recruitment. Importantly, this phase does not automatically dissipate after the initial injury has been resolved, but rather an active resolution must be initiated 19,40. Inflammatory resolution is regulated by SPMs: the ω3-polyunsaturated fatty acid (PUFA)-derived protectins, resolvins and maresins, and the ω6-PUFA-derived LXA4 and LXB419,41,42. In addition, the peptide Annexin A1 (AnxA1) is an important endogenous regulator of inflammatory resolution 43,44. Both LXA4 and AnxA1 activate the FPR2/ALX G-protein coupled receptor, although the LXB4 receptor remains to be identified 19,41,42. Together, these proresolving mediators attenuate neutrophil recruitment, while inducing a proresolving M2 MΦ phenotype, thus promoting MΦ-mediated phagocytosis of apoptotic cells (efferocytosis) and inflammatory resolution 41. Impaired inflammatory resolution may underlie the pathogenesis of chronic inflammatory disorders, such as metabolic syndrome, diabetes, and CVD 45,46. The therapeutic potential of using SPMs to promote resolution and overcome chronic inflammation and disease has therefore been highlighted 8,19,43,47–51.
The chronic inflammation characterizing cardiometabolic pathophysiology may indeed reflect defective resolution 45. However, it is important to note that endogenous resolution is not always impaired. As an example, 30% of obese patients appear to remain ‘metabolically healthy’, that is, lacking metabolic disorders (diabetes, dyslipidemia, hypertension) 52, which may be because of an enhanced endogenous ability to initiate resolution. Similarly, atherosclerotic lesions often undergo partial resolution, characterized by the formation of the fibrous cap that provides a barrier between the prothrombotic plaque and the platelets in the blood stream, and thus most atherosclerotic plaques do not cause acute vascular disease 53. It is therefore possible that cardiometabolic morbidity and mortality may be reduced by strengthening the patients’ endogenous ability to resolve inflammation. Importantly, such therapeutic approaches would likely have few side effects and provide long-term safety with respect to CVD. The ω3-PUFA-derived SPMs attenuate obesity-induced adipose inflammation and related liver disease 54–58 as well as many features of CVD (for review articles, see 22,40,59,60). Similarly, AnxA1 correlates with reduced adipose inflammation and protects against nonalcoholic steatohepatitis 61,62. Furthermore, AnxA1 may protect against myocardial infarction 63 and when using collagen IV-targeted nanoparticles to deliver Ac2-26 (the N-terminal derived peptide of AnxA1) to the advanced atherosclerotic lesions of fat-fed Ldlr−/− mice, Ac2-26 promotes plaque stability while decreasing oxidative stress and plaque necrosis 64. Recent evidence also shows the therapeutic potential of LXs in cardiometabolic disease, as outlined below.
Lipoxins in atherosclerosis and cardiovascular disease
Inflammation plays a crucial role in atherosclerotic plaque formation and CVD, as outlined above, and the therapeutic potential of LXs has been highlighted as they may promote the resolution of atherosclerotic plaques and increase plaque stability 2,19,27,40,65 (Fig. 1). Indeed, patients with symptomatic peripheral artery disease have lower levels of aspirin-triggered LXs 66 and chronic heart failure is associated with reduced LX levels in plasma and urine 67. Interestingly, SPMs derived from perivascular adipose tissue may influence the inflammatory resolution of atherosclerotic plaques 68. Furthermore, LXs reduce reperfusion-associated vascular inflammation 69 and protect cardiomyocytes by modulating potassium channels 70 and activating p38 MAPK pathways and nuclear translocation of Nrf2, which induces the release of the protective hemeoxygenase-1 71.
An initiating factor in the atherosclerotic process is the activation of endothelial cells, which upregulate adhesion molecules utilized by leukocytes to enter the arterial intima. LXs inhibit angiogenic pathways, including endothelial proliferation and activation 72–75. LXs reduce P-selectin expression in human aortic endothelial cells 76,77 and attenuate P-selectin-mediated neutrophil–endothelial interactions 78. LXs also inhibit neutrophil chemotaxis, adhesion, and transmigration 79, and reduce proinflammatory cytokine secretion 80 and ROS production 79,81,82. Finally, a recent study showed that LXs attenuate neutrophil NET formation 83. NETs play a critical role in atherosclerosis by activating DCs to produce IL-12, thus driving Th1 cellular responses 84, for instance, IFN-γ production that stimulates an M1 MΦ phenotype and foam cell formation 85. Indeed, the LX-mediated attenuation of NET formation is worthy of further investigation.
The importance of the monocyte phenotype in the atherosclerotic process has received considerable attention, although the knowledge of the field is continuously evolving. The murine monocytes are commonly classified as inflammatory Ly6Chi versus the less inflammatory Ly6lo. Interestingly, the inflammatory Ly6Chi monocytes appear to be particularly important in the onset of atherosclerosis, although the maximal inhibition of atherosclerosis is achieved when blocking all monocyte recruitment 86. Importantly, similar subsets of monocytes exist in humans, often characterized as classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) subsets, where the classical CD14++CD16− correspond to the Ly6Chi subset, although it is not yet clear how these contribute toward the atherosclerotic process in humans. It is noteworthy that LXs specifically attract ‘anti-inflammatory’ monocytes to inflammatory sites, which are characterized by reduced ROS production as they migrate to the tissue 87, and LXs decrease monocyte IL-1β and calcium influx 88.
Similar to the monocytes, MΦs may be subphenotyped into several classes, showing inflammatory, proresolving, and/or wound-healing properties depending on their phenotype. MΦs are commonly characterized as ‘inflammatory M1’ versus ‘anti-inflammatory M2’, where the former are proatherogenic and the latter are antiatherogenic. Admittedly, this is an oversimplification as several other MΦ phenotypes are of critical importance to the atherosclerotic process and inflammation 26,27,32. However, for this review, we will refer to the M1/M2 nomenclature. One of the cardinal effects of LXs is that they promote a ‘proresolving’ M2 MΦ phenotype, which correlate with decreased production of proinflammatory mediators, for example, TNF-α, IL-6, and nuclear factor (NF)-κβ activation, whereas the anti-inflammatory milieu is promoted by increased TGF-β1 and IL-10 levels 62,80,89–91. A critical result of this phenotypic switch is improved efferocytosis as LXs remodel the MΦ cytoskeleton to promote their engulfment of apoptotic cells 92–95. Finally, LXs reduce MΦ apoptosis 96, which may enable the cells to perform their cellular functions for longer. As impaired efferocytosis and premature MΦ necroptosis are proatherogenic effects, the LX-mediated shift in the MΦ phenotype and function is noteworthy. LXs may also act as antiatherogenic agents by promoting anti-inflammatory characteristics of other leukocytes. Indeed, LXs enhance CCR5 expression on apoptotic neutrophils and T-cells, which promotes inflammatory resolution by acting as a decoy receptor for CCL3, CCL4, and CCL5, thus terminating chemokine signaling 97. Furthermore, LXs decrease the proliferation, and IgG and IgM production of human memory B-cells, thereby downregulating NF-κB p65 nuclear translocation in an ALX/FPR2-dependent manner 98, which may reduce oxLDL opsonization and foam cell formation.
The liver plays a critical role in the atherosclerotic process as hepatic C-reactive protein increases the endothelial expression of adhesion molecules, thus amplifying the inflammatory response. Cholesterol metabolism is closely interlinked with CVD and statins promote a favorably LDL-cholesterol and HDL-cholesterol ratio, which attenuates cardiovascular pathophysiology. Interestingly, a recent study by Demetz et al.99 shows that the arachidonic acid metabolome is an important regulator of cholesterol homeostasis. Aspirin-induced LXs increase hepatic expression of the bile salt export pump ABCB11, which translates into enhanced reverse cholesterol transport, a key function of HDL. LX mimetics also lower plasma LDL-cholesterol 99 and reduce obesity-induced elevation of serum alanine aminotransferase and hepatic steatosis through reduction of adipose inflammation and a subsequent increase in AnxA1 62. Furthermore, LXs enhance organ function in murine liver transplantation, decreasing IFN-γ while increasing IL-10 100,101.
If an atherosclerotic plaque ruptures, a thrombus may form and plaque stability is therefore of great importance to the clinical care of patients. Inflammatory mediators regulate the matrix-degrading proteinases that contribute toward the dissolution of interstitial collagen, thus thinning and weakening the fibrous cap 102. LXs inhibit IL-1β-induced IL-6, IL-8, and MMP-3 production in human fibroblasts and furthermore enhance the synthesis of MMP inhibitors 103, which may promote plaque stabilization. Furthermore, LXs modulate platelet-derived growth factor-stimulated migration of vascular SMCs isolated from human saphenous veins 66. Interestingly, the pluripotent FPR2/ALX receptor may play a dual role in atherosclerosis, promoting disease progression through proatherogenic effects on bone marrow-derived cells, but increasing plaque stability by promoting SMC collagen synthesis and cross-linking 104. In this context, it is worth highlighting that the characteristic expression of SMC and MΦ surface markers may be altered in the pathophysiological milieu of the atherosclerotic plaque so that MΦs may express SMC markers (e.g. α-actin and SM22α) and SMCs may express traditional MΦ markers (e.g. CD68 and Mac2) 2. This is noteworthy when interpreting the literature of the field as SMCs and MΦs may have been misidentified in previous studies.
Finally, circulating bacteria may contribute toward atherogenesis. For instance, the periodontal pathogen Porphyromonas gingivalis causes platelet aggregation and contributes toward CVD in mice 105–110 and the bacterium has been found in human atherosclerotic plaques 111,112. In this context, it is noteworthy that LXs reduce P. gingivalis-induced neutrophil–platelet aggregation and ROS production in human whole blood by downregulating neutrophil CD11b/CD18 expression and its high-affinity epitope 82. Furthermore, LXs inhibit P. gingivalis-induced neutrophil influx, COX-2 expression, and PGE2 secretion in the periodontal cavity of mice, without promoting further spread of the infection 113. In addition, LXs may act as a vasodilator by promoting endothelial release of prostacyclin and nitric oxide, while inhibiting ROS production 114–116, highlighting that LXs may have therapeutic potential in attenuating acute cardiovascular events.
Lipoxins in metabolism and adipose inflammation
It is well-established that white adipose tissue (WAT) is not merely an insulating energy store but also an endocrine organ regulating appetite, glucose and lipid metabolism, blood pressure, inflammation, and immune function 117. As outlined in the introduction, prolonged obesity causes a state of systemic low-grade inflammation, resulting in insulin resistance, metabolic syndrome, and pathologies such as T2DM, atherosclerosis, and nonalcoholic fatty liver disease 118. As detailed below, LXs promotes resolution of adipose inflammation and protects against obesity-induced metabolic disease (for reviews see 17,40,51). Importantly, the FPR2/ALX receptor is expressed in both human and mouse adipose tissue 57,119.
LXs promote the resolution of adipose inflammation by inducing an M1-to-M2 MΦ phenotype switch. We first showed this in a model of age-associated adipose inflammation 119, representing a chronic, low-grade inflammation similar to obesity and T2DM-associated inflammation 120. In this model, LX attenuated IL-6 and increased IL-10 expression 119. The altered cytokine milieu correlated with increased glucose transporter type 4 (GLUT-4) and insulin receptor substrate-1 (IRS-1) expression, suggesting improved insulin sensitivity. In-vitro studies confirmed that LX rescued MΦ-induced desensitization to insulin-stimulated signaling and restored 3H-glucose uptake in cultured adipocytes. This was associated with preservation of AKT activation and reduced secretion of proinflammatory cytokines, including TNF-α 119.
Similarly, in a model of diet-induced obesity, interventional treatment with LXs promotes an adipose M1-to-M2 MΦs phenotype switch, inhibiting CD11c+ M1 MΦs and TNF-α, while restoring CD206+ M2 MΦs and increasing AnxA1 production 62. Early studies have suggested that LXs might mediate protection against disease by inducing the production of the protective hormone adiponectin 57. However, increased adiponectin levels appear to be a consequence of an ‘overall’ improved adipose milieu, rather than a direct stimulation, as LX-mediated protection is sustained in Adiponectin−/− mice 62. Furthermore, LXs did not induce adiponectin production in cultured 3T3-L1 adipocytes 62. Interestingly, LXs did not enhance obesity-induced impairment of glucose tolerance in the obese C57BL/6J mice, indicating that the lipid may not affect pancreatic insulin function 62. However, LXs reduced fasting glucose in Adiponectin−/− mice 62 and rescued 3H-glucose uptake in cultured adipocytes 119, suggesting that the lipid may exert some modulation of insulin resistance. In the experimental obesity model, LX-induced restoration of WAT function resulted in protection against systemic kidney and liver disease 62. Importantly, LX-mediated protection against obesity-induced pathologies occurred without affecting total body weight 62, suggesting that LXs may promote a ‘metabolically healthy phenotype’, which, in humans, can provide protection against, for example, cardiometabolic pathophysiology and reduce obesity-related mortality 3,4,121, although this remains to be investigated.
It is important to highlight that WAT is comprised of a heterogeneous composition of cells: 60% adipocytes and a 40% stromal-vascular compartment, the latter composed of preadipocytes, leukocytes, fibroblasts, and endothelial cells 122. In the scientific field, particular focus has been directed toward MΦs as critical effector cells initiating WAT inflammation and insulin resistance, and indeed MΦ depletion attenuates obesity-induced insulin resistance 23,25,123–125. However, T-cells, B-cells, NK-cells, and DCs are also important regulators of adipose inflammation 126 and neutrophils mediate insulin resistance in obese mice 127. It is noteworthy that in addition to their well-established actions on leukocytes 49, LXs affect numerous cell types, including adipocytes 119. Indeed, LXA4-mediated attenuation of WAT inflammation occurs through modulation of both MΦ and adipocyte cell signaling 119 (Fig. 2). As evidence of the latter, cultured 3T3-L1 adipocytes express the murine equivalent of the FPR2/ALX receptor Fpr3/Fpr-rs2 119 and when stimulated with LXA4, adipocytes resist TNF-α induced impairment of insulin-stimulated GLUT-4 translocation 119. Again, a key mechanism involves LX-mediated restoration of AKT activation: a ubiquitous serine/threonine kinase regulating metabolism and apoptosis. Insulin-induced AKT phosphorylation enables translocation of GLUT-4 to the plasma membrane and thus cellular glucose uptake. Interestingly, when LXA4 mediates protection through MΦs, AKT phosphorylation is restored both at the Serine473 and at the Threonine308 site 119. However, adipocytes incubated directly with LXA4 only show restored phosphorylation at the threonine 308 site, indicating a specific signaling pathway 119. Finally, it is quite possible that LXs, in addition to modulating MΦs and adipocytes, might affect additional WAT cells, both of myeloid and of nonmyeloid origin, for example, T-cell subsets, B-cells, fibroblasts, and possibly also preadipocyte differentiation. Studies investigating these possibilities would be valuable to the scientific community.
Interesting, our recent findings indicate that LXs may modulate obesity-induced adipose autophagy 62, which may impact adipose inflammation and metabolic pathophysiology. The role of autophagy in adipose inflammation is complex, but the current consensus is that chronic obesity causes excessive activation of autophagy in the adipose tissue, which correlates with increased cell death and adipose inflammation 128–130. Obesity is associated with enhanced levels of WAT autophagy, as evidenced from decreased p62 and LC3-II levels, suggesting high autophagy flux and enhanced degradation of the proteins. LXs restore obesity-induced attenuation of p62 and LC3-II protein to the levels observed in lean mice 62. The mechanisms appear to be mTOR and AMPK independent 62, but it is unknown whether LXs affect autophagosome maturation (fusion of autophagosomes with lysosome). Thus, future studies are needed to detail the molecular mechanisms involved in LX-mediated regulation of autophagy and its significance to adipose inflammation. In addition, it is noteworthy that p62/SQSTM1 has been identified as one of the key proteins that promote lipid metabolism and limit inflammation in the recently identified ‘metabolically activated’ MΦ (mMe-MΦ) 131. Activation of p62 results in inhibition of NF-κβ and thus limits inflammation. The LX-mediated restoration of p62 activity may thus not only interlink with autophagy, but may promote the anti-inflammatory mMe-MΦ population, although this remains to be further investigated in future work.
The prevalence of cardiometabolic disease is increasing, with severe socioeconomic implications. Inflammation is a common denominator is both metabolic and cardiovascular disease and promoting inflammatory resolution may thus be a useful therapeutic approach. The endogenously produced LXs likely have few side effects and, by promoting inflammatory resolution in adipose tissue and atherosclerotic plaques, while inhibiting angiogenic pathways and neutrophil–platelet aggregation, LXs may have therapeutic potential in cardiometabolic disease.
E.B. is funded by a Marie Curie International Outgoing Fellowship (GA-2011-301803).
Conflicts of interest
There are no conflicts of interest.
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