Increasing clinical observation suggested the involvement of inflammation in the pathogenesis of various cardiovascular diseases. Extensive recruitment and infiltration of blood-derived inflammatory cells such as granulocytes and macrophages into the vessel wall has been considered as a pathological marker in the active stages of atherosclerosis. The activated inflammatory cells also have been recorded in the patients with angina and other ischemia heart diseases. Upregulation of inflammatory mediators in blood vessels, such as transcription factors nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule and tissue factor, has been reported in experimental hypertension models.1 Although most investigations have focused on the vasculature as a key target of inflammatory and oxidative insults, other organs are also participated in the pathological progress of hypertension. Cardiac hypertrophy and myocardial infarction, stroke, and renal failure are common clinical complications associated with the development and progression of hypertension. Accordingly, we evaluated inflammatory status in important organs (kidney, liver, heart, and brain) in spontaneously hypertensive rats (SHR), the genetic animal model of hypertension.
The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. It is now accepted that there are three related but quite distinct PPARs: PPARα, PPARβ/δ, and PPARγ. PPARs are initially believed to regulate genes involved only in lipid and glucose metabolism. However, the roles of PPARs evolve quickly which affect numerous processes ranging from carcinogenesis to inflammation. Furthermore, activation of PPARs has been shown to have antihypertensive effects in both human and animal models.2-5 Raji et al2 reported that rosiglitazone (PPARγ agonist) reduced systolic and diastolic blood pressure, improved insulin sensitivity, and induced favorable changes in cardiovascular risk markers in hypertensive patients. Another PPARγ activator pioglitazone has been found to lower blood pressure in hypertensive patients without diabetes,3 thus, a non-glycemic effect of PPAR agonists is suggested. One of mechanisms underlying the beneficial effects of PPARs beyond glucose metabolism may relate to their anti-inflammatory and antioxidant actions.4 Activation of both PPARα and PPARγ have been shown to not only antagonize angiotensin II (Ang II) actions, but also inhibit reactive oxygen species (ROS), decrease reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity as well as attenuate proinflammatory mediators and adhesion molecules in blood vessels from hypertension individual and animal model.4,5 PPARβ/δ also exhibits anti-inflammatory properties by inhibiting expression of VCAM-1 and monocyte chemoattractant protein-1 (MCP-1).6 Although higher levels of both PPARα and PPARγ have been detected in blood vessels of SHR comparing that in normotensive Wistar-Kyoto rats (WKY),7 few data are available concerning PPAR isoforms expression in different tissues of hypertension beyond vasculature. In current study, we detected the expression of three PPAR isoforms and their target genes in the kidney, liver, heart, and brain of SHR. We also observed the expression of nuclear factor CCAAT/enhancer-binding protein δ (C/EBPδ), which can trans-activate PPARγ expression in vascular smooth muscle cell (VSMC).8
Reagent was purchased from Sigma-Aldrich (USA). Antibodies for rat iNOS, ICAM-1, PPARα, PPARβ, PPARγ and C/EBPδ were obtained from Santa Cruz Biotechnology Inc. (USA). Antibody for nitrotyrosine was from Cayman Chemical (USA). Reverse transcription-polymerase chain reaction (RT-PCR) reagents were purchased from BioDev-Tech (China). Primers were synthesized by Sangon (China). All the other chemicals were of analytical grade.
Animals and tissue preparation
Male WKY and SHR at the age of 20 weeks (n=6) were purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences and housed with free access to water and food. The rats were anaesthetized with 50 mg/kg sodium pentobarbital (i.p.) and sacrificed by bleeding from the carotid artery according to the Shanghai University of Traditional Chinese Medicine guidelines for the approved use of experimental animals. The kidney, liver, heart, and brain were quickly isolated. All tissues were immediately frozen in liquid nitrogen, and stored at -135°C until further processing.
Blood pressure measurement
Systolic blood pressure (SBP) of both SHR and WKY rats was measured using tail-cuff plethysmography in unanesthetized prewarmed trained rats. Rats were trained to lie quietly in a restrainer placed on a warm pad for a period of at least 30 minutes for 3 days before the study. On the day of the study, the rats were placed in the temperature-controlled restrainer for 10 minutes. Blood pressure was then measured repeatedly and averaged from five consecutive measurements.
Total RNA isolation and RT-PCR amplification
RNA isolation was performed according to the manufacturer's instructions. In brief, 100 mg frozen tissues were pulverized in liquid nitrogen and homogenized in 1 ml of Tri reagent (Sigma), chloroform extracted, and total RNA was precipitated in isopropanol, then washed with 80% and 100% ethanol. The dried RNA pellet was dissolved in distilled water and quantified by the absorbance at OD260. RNA solution was used to conduct RT-PCR.
RT-PCR analysis of proinflammatory gene transcript and PPARs was conducted as follows: 1.5 μg of total RNA was subjected to reverse transcription to synthesize complementary DNA chain with oligo dT16 primer. The synthetic heterodimers were amplified by polymerase chain reaction. The sequences of primers for interleukin-1 beta (IL-1β) were 5′-CCTGTGGCCTTGGGCCTCAA-3′ and 5′-GGTGCTGATGTACCAGTTGGG-3′, for tumor necrosis factor alpha (TNFα) were 5′-CCCTCACACTC-AGATCATCTTCTCAA-3′ and 5′-TCTAAGTACTTGG-GCAGGTTGACCTC-3′, for ICAM-1 were 5′-GCGGC-CTTGGAGGTGGAT-3′ and 5′-GGAGGCGGGGCTTG-TACC-3′, for inducible nitric oxide synthase (iNOS) were 5′-CCAACCGGAGAAGGGGACGAACT-3′ and 5′-GGAGGGTGGTGCGGCTGGAC-3′, for VCAM-1 were 5′-CCTGTCCCAGAGGAGGGC-3′ and 5′-CAAC-TGCGAGCCGACTTCG-3′, for E-selectin were 5′-GCACCACAGCGAGGCCAC-3′ and 5′-CGGGGAGG-GTTGGCTGGG-3′, for PPARα were 5′-CCAGTATTT-AGGAAGCTGTCC-3′ and 5′-AAGTTCTTCAAGTAG-GCCTCG-3′, for PPARβ were 5′-AGATCAGCGTGC-ATGTGTTC-3′ and 5′-GAAGAGGTACTGGCTGTCG-G-3′, for PPARγ were 5′-GAGATGCCATTCTGGCCC-ACCAACTTCGG-3′ and 5′-TATCATAAATAAGCT-TCAATCGGATGGTTC-3′. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control. The RT-PCR product was applied on 1.2% agarose gel. After electrophoresis in 1×TAE buffer, gel was photographed. Band intensity was measured with TANON Gel Image Analysis Software (China). Data were normalized with GAPDH intensity.
Protein extraction and Western blotting
The tissues were homogenized at 4°C in PBS (pH 7.4) containing protease inhibitors (final concentration: 10 μg/ml soybean trypsin inhibitor/10 μg/ml benzamadine/ 0.005 U/ml trypsin inhibitor aprotinin/10 μg/ml leupeptin/10 μg/ml pepstatin A/5 μg/ml antipain/0.2 mmol/L PMSF/0.1 mmol/L ethylene diamine tetraacetic acid). Each sample was homogenized using a polytron at 0°C, then sonicated on ice using a cell disrupter with five pulses at duty cycle of 40% and output of 3. The homogenates were centrifuged at 3000 ×g for 15 minutes at 4°C, and supernatant was obtained. Proteins were loaded and separated on a 10% SDS-PAGE and transferred onto nitrocellulose membrane. The membrane was blocked with a solution of 0.1% Tween 20/PBS (PBS-T) containing 5% fat-free milk for 1 hour, then incubated with the primary antibody for 2 hours at room temperature followed by washing for 3×10 minutes with PBS-T buffer. The blot was re-incubated with horseradish peroxidase conjugated secondary antibody for 1 hour at room temperature. After washed 3×10 minutes with PBS-T, the membrane was visualized by chemiluminescence. Protein levels were measured by Lowry assay.
Detection of carbonyl formation with spectrophotometer
Oxidative damage of protein is often accompanied by the formation of protein carbonyl groups that has been used widely as an index of protein oxidation. Protein carbonyls were determined by the spectrophotometric measurement of the formation of 2,4-dinitrophenylhydrazone derivatives (ε370 nm=22 000 mol·L-1·cm-1).9 After removal of nucleic acids with streptomycin sulfate, the proteins in the homogenates from the kidney, liver, heart, and brain were divided equally and incubated with 2,4-dintrophenylhydrazine (DNPH, in HCl) and HCl, respectively, at room temperature. Protein oxidation (carbonyls) was determined by the absorbance of DNPH samples at A370. The protein concentration was calculated from the A280 of the HCl samples. Data are presented as nmol/mg protein.
The experimental data were expressed as mean ± standard deviation (SD) and SPSS 10.0 software package was used for data processing. The mean values for SHR group were compared with those for the control WKY group using Student's t test; P values of less than 0.05 were considered statistically significant. The 6 animals per group were used in the experiment.
Body weight and systolic blood pressure
SHR and WKY with similar body weight ((250±10) g) have been used for experiment. SHR presented higher SBP levels than WKY ((200.6±7.3) vs (128.0±5.8) mmHg, P<0.01).
Proinflammatory profile in different organs of WKY and SHR
Proinflammatory cytokines IL-1β and TNFα, adhesion molecules ICAM-1, VCAM-1, and E-selectin, and iNOS expression were analyzed in the kidney, liver, heart, and brain. Semiquantitative RT-PCR analysis demonstrated significant upregulation of these proinflammatory mediators in the most organs of SHR, as compared with WKY (P <0.05, Figure 1). However, IL-1β in the liver and brain as well as iNOS in the brain of SHR failed to show clear differences. mRNA expression of E-selectin in the brain was undetectable in both SHR and WKY, probably due to the selective expression in different organs. As shown in Figure 2, the protein expressions of iNOS and ICAM-1 were barely detected in the organs of normotensive WKY, while hypertension increased iNOS and ICAM-1 expression in the kidney, liver, and heart of SHR significantly (P <0.05).
Formation of carbonyl and nitrated proteins in WKY and SHR
Oxidative processes are considered to play a crucial role in inflammatory processes. The “cross-talk” between the activation of inflammatory response and oxidative stress forms the base for further stimulation of downstream signaling pathways and pathogenesis consequences. Protein carbonylation is the result of oxidative modification of protein by ROS. As shown in Figure 3A, significantly higher values of protein carbonyl were observed in the kidney, heart, and brain of SHR compared to WKY (P <0.05). There was a tendency for the level to increase in the liver of SHR, but not statistically significant.
Moreover, increased ROS can react rapidly with nitric oxide (NO) yielding peroxynitrite, a highly cytotoxic reactive nitrogen species (RNS). In the present study, the putative peroxynitrite marker nitrotyrosine was identified by Western blotting analysis using a monoclonal antibody. As can be seen in Figure 3B, significant nitrotyrosinated protein could be detected in the kidney, liver, and heart of SHR in comparison to control WKY. However, in the organ of brain, there was no significant difference between protein nitration for SHR and WKY rats.
Expression of PPARs in different organs of WKY and SHR
Three PPAR isoforms, α, β/δ, and γ, have been identified in PPARs. Compared to WKY, transcription and protein levels of PPARα, PPARβ/δ, and PPARγ were considerably higher in all tested organs of SHR (P <0.05) (Figure 4). Specifically, the protein expression of PPARα was increased by 130.76%, 91.48%, 306.24%, and 90.70%; PPARβ/δ by 109.34%, 161.98%, 137.04%, and 131.66%; PPARγ by 393.76%, 193.17%, 559.29%, and 591.18% in the kidney, liver, heart, and brain, respectively (Figure 4B).
Activation of PPARs can result in upregulation of their target genes expression. We have evaluated mRNA expression of PPARα target gene acyl-CoA oxidase10 and PPARγ target gene CD36.11Figure 5A demonstrated that the transcription of these two PPAR-response genes was significantly increased (P <0.05) in the kidney, liver, heart and brain of SHR, which was in consistent with the changes of PPARα and PPARγ expression.
Recent studies have demonstrated that PPARγ gene promoter has tandem repeats of C/EBP-binding motif, and C/EBPδ plays a central role in transactivation of the PPARγ gene.12,13 Thus, we also observed the expression of nuclear factor C/EBPδ in various organs of SHR and WKY. As shown in Figure 5B, in line with the changes in PPARγ, protein expression of C/EBPδ were markedly elevated (P <0.05) in the tested organs of SHR.
Hypertension injures blood vessels and thereby causes end-organ damage. The present study addressed an elevated inflammatory status in different organs of SHR. Increased expression of proinflammatory mediators and enhanced protein oxidation/nitration observed in SHR reflected a promoted inflammation and an elevated oxidative stress in the kidney, liver, heart, and brain, which might result in the secondary organ damage associated with the primary disease.
Inflammatory damage is often accompanied by the over generation of ROS, which can attack cellular components such as lipids, proteins, and nucleic acids. In deed, in our study, biochemical analyses of tissue proteins showed significant elevation of carbonyl groups in the kidney, heart, and brain of hypertensive rats in comparison to healthy controls (Figure 3A). We did not detect the significant increase of carbonyl protein in the liver (Figure 3A) in current study which may be due to an elevated antioxidative status of the organ. It has known that as a major endogenous antioxidant agent, glutathione (GSH) is mainly produced by the liver,14 indicating the liver may be more resistant to oxidative modification.
Furthermore, increased superoxide can also react rapidly with NO, not only inactivating NO but generating peroxynitrite, a more toxic and reactive molecule. The reduced bioavailability of NO has been associated with reduced vasorelaxation and increased leukocyte adhesion and platelet aggregation.15 Peroxynitrite can initiate multiple pathologic processes with its powerful oxidative activity such as inhibition of key metabolic enzymes, oxidation of lipid, nitration of the protein tyrosine residues, reduction of cellular antioxidant defenses by oxidation of thiol pools, and induction of DNA strand breaks, leading to apoptosis.16,17 Among them, level of nitrotyrosine is considered as an indicator for peroxynitrite generation.18 The simultaneous induction of iNOS and nitrotyrosine in SHR in our experiment indicated that NO produced in the organs might couple to the production of peroxynitrite. The absence of protein nitration in the brain of SHR may reflect the fact that iNOS expression was also not observed in the brain of hypertensive rats in the current study.
In the present study, the expression of three PPAR isotypes (PPARα, β/δ, and γ) were significantly increased in all the tested organs of SHR. However, previous report by Diep et al7 demonstrated that in the heart, kidney, and liver, there was no significant differences in both PPARα and PPARγ between WKY and SHR. One possible explanation for this discrepancy is that SHR and WKY used in Diep and coworkers’ study were 4 weeks younger and SBP was much lower than ours ((187.5±4.7) vs (200.6±7.3) mmHg). Thus, PPARs could be modulated in SHR upon the different age and development of high blood pressure. In addition, the most previous studies primarily focus on the detection of PPARα and γ subtypes in various models of hypertension. Few data are available concerning PPARβ/δ expression in this disease. Our data demonstrated for the first time that the expression of PPARβ/δ, like PPARα and PPARγ, was also enhanced in the tissues of SHR.
The inhibitory effects of PPARs on inflammation have been shown to play a crucial role in their anti-hypertensive and organ-protective actions.4,5 PPARα activator fenofibrate reduces myocardial fibrosis resulted from hypertensive heart disease and prevents the development of diastolic dysfunction in DOCA-salt hypertensive rats.19 Stroke has been known as a severe complication of hypertension. Administration of PPARγ ligand, rosiglitazone or pioglitazone dramatically reduces infarction volume and improves neurological function following middle cerebral artery occlusion in rats via ameliorating expression of these inflammatory mediators.20,21 Renal fibrosis is another major complication associated with the development and progression of hypertension. The structure injury that leads to progressive loss of renal function consists of glomerulosclerosis and tubulointerstitial fibrosis and atrophy.22 Treatment of PPARγ agonist, troglitazone alone has been shown to significantly ameliorate the progression of glomerulosclerosis in a rat model of hypertensive glomerulosclerosis.23 Thus, agonist of PPARs is probably a potential therapeutic agent for secondary organ complications associated with hypertension.
Given the anti-inflammation actions of PPARs, the severe inflammatory status in primary hypertension disease is hypothesized to be accompanied by reduced tissue expression of PPARs. However, the major organs (kidney, liver, heart, and brain) of SHR in our study demonstrated considerably enhanced expression of PPARs. This paradox has also been reported by Diep et al7 in blood vessels of SHR. We propose that the increased expression of PPARs may reflect a feedback mechanism towards elevated inflammatory response. Similar response of PPARs has also been observed in other inflammation-related diseases. For instance, inflammatory mediators are involved in brain ischemia injury. Focal cerebral ischemia induced by middle cerebral arteries occlusion (MCAO) led to up-regulation of PPARγ messenger RNA in neurons of the ischemic hemisphere, and treatment with PPARγ agonists reduced inflammation and infarction size.24 In ovalbumin-induced asthma, PPARγ levels were significantly increased in the inflammatory airway and lung tissues.25 Thus, upregulation of PPARs in tissues may represent one of body self-protective mechanisms against inflammatory injury.
In addition to the elevation of PPARs, increased levels of PPAR-responsive genes acyl-CoA oxidase and CD36 were also observed in our study. It is possible that the up-regulation of acyl-CoA oxidase and CD36 gene expression in the organs is due to activation of elevated PPARs by their endogenous ligands. Although we did not observe the changes of PPARs endogenous ligands, it has been shown that the plasma levels of 15-dPGJ2, natural endogenous ligand for PPARγ, are elevated within 24 hours in patients after an acute stroke and during the resolution phase of inflammation in rats with carrageenin-induced pleurisy.26,27 However, the intensive inflammatory response of the hypertensive organs in our study suggests the levels of endogenous PPARs ligands could be relatively insufficient. Further studies, both in vitro and in vivo, are warranted to investigate the beneficial effects of exogenous PPARs activators on the organs of hypertension.
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Keywords:© 2008 Chinese Medical Association
spontaneously hypertensive rats; inflammation; peroxisome proliferator-activated receptors