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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptors (PPARs) belongs to the nuclear hormone receptor superfamily. So far three different subtypes of PPAR (alpha, gamma, and delta (beta)) have been identified in amphibians, chicken, rodents and man. These receptors are transcription factors that control the beta-oxidation and transport pathways of fatty acids and adipocyte differentiation containing fatty acid synthesis under the modification of PPAR activation with CBP and its analogs. Thus, PPARs play an important role in lipid metabolism. Furthermore, altered fatty acid levels are associated with obesity, diabetes, hypertension and atherosclerosis, so PPARs may serve as molecular sensors in these metabolic disorders.
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PMID:[Lipid metabolism related nuclear receptor--the structure, function, expression and classification of peroxisome proliferation-activated receptor (PPAR)]. 970 44

Endothelin-1 (ET-1), a 21-amino acid vasoactive peptide mainly produced by vascular endothelial cells, is involved in the regulation of vascular tone and smooth muscle cell proliferation. Peroxisome proliferator-activated receptors (PPARs), key players in lipid and glucose metabolism, have been implicated in metabolic disorders that are predisposing to atherosclerosis. Because of the potential role of ET-1 in vascular disorders such as hypertension and atherosclerosis, we investigated the regulation of ET-1 expression by PPAR activators. Western blot and reverse transcription-polymerase chain reaction analyses demonstrated that both PPARalpha and PPARgamma are expressed in human coronary artery endothelial cells as well as in endothelial cell lines such as HMEC-1 and ECV304. In bovine aortic endothelial cells and HMEC-1 cells, both PPARalpha and PPARgamma ligands inhibited thrombin-induced ET-1 secretion, whereas basal ET-1 secretion was only slightly suppressed. Reverse transcription-polymerase chain reaction experiments showed that this inhibition of ET-1 production occurs at the gene expression level. Using transient transfection assays, we demonstrated that PPARs downregulate thrombin-activated transcription of the human ET-1 promoter. Transactivation studies with c-Jun and c-Fos expression plasmids indicated that PPARs negatively interfere with the activator protein-1 signaling pathway, which mediates thrombin activation of ET-1 gene transcription. Furthermore, electrophoretic mobility shift assays demonstrated that PPAR activators reduce the thrombin-stimulated binding activity of bovine aortic endothelial cell nuclear extracts as well as c-Jun binding to an activator protein-1 consensus site. Taken together, these data indicate that (1) both PPARalpha and PPARgamma are expressed in human vascular endothelial cells and (2) PPAR activators inhibit thrombin-induced ET-1 biosynthesis, indicating a novel role for PPARs in vascular endothelial function.
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PMID:Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. 1047 69

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a key player in glucose metabolism. If PPARgamma ligands modulate nitric oxide (NO) synthesis in the vascular tissue, they may affect the process of plaque formation and postangioplasty restenosis. We investigated the effects of PPARgamma ligands on NO synthesis in vascular smooth muscle cells. Incubation of cultures with interleukin-1beta (10 ng/mL) for 24 hours caused a significant increase in the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells. The PPARgamma agonists troglitazone and 15-deoxy-triangle up(12,14)-prostaglandin J(2) (15d-PG J(2)) dose-dependently inhibited nitrite production by interleukin-1beta-stimulated vascular smooth muscle cells. Decreased interleukin-1beta-induced nitrite production by the PPARgamma agonists was accompanied by decreased inducible NO synthase mRNA and protein accumulation. Interleukin-1beta induced nuclear factor-kappaB activation in vascular smooth muscle cells, and both troglitazone and 15d-PG J(2) markedly suppressed this nuclear factor-kappaB activation. PPARgamma ligands inhibit NO synthesis in cytokine-stimulated vascular smooth muscle cells, suggesting that these agonists may act directly on the vascular smooth muscle and influence the process of atherosclerosis and restenosis.
Hypertension 2000 Jun
PMID:Peroxisome proliferator-activated receptor-gamma ligands inhibit nitric oxide synthesis in vascular smooth muscle cells. 1085 69

The expression of genes encoding fatty acid utilization enzymes is coordinately downregulated during the development of cardiac hypertrophy and failure. However, molecular mechanisms that mediate this downregulation are unknown. Peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) have been identified in promoters of many genes involved in fatty acid utilization, where they function as positive regulatory elements. PPARs bind to PPREs as heterodimers with retinoid X receptors (RXRs). Primary cardiac myocytes from neonatal rats were transfected with a reporter construct driven by the C promoter of rat acyl-coenzyme A synthetase (ACS) gene. Stimulation with phenylephrine, a potent inducer of hypertrophy, markedly downregulated the activity of this promoter. By use of electrophoretic mobility-shift assays (EMSAs) using PPRE in the rat ACS promoter as a probe, we found a sequence-specific protein-DNA complex in the nuclear extract from adult rat left ventricular (LV) myocardium. Supershift experiments revealed that this complex was immunoreactive for PPARalpha and RXRalpha. We compared the activity of this complex in LV nuclear extracts from Dahl salt-sensitive rats (DSs) with hypertension and control age-matched Dahl salt-resistant rats (DRs). Even at the stage of concentric LV hypertrophy with normal systolic function, the activity of the band was markedly diminished in DSs compared with DRs. However, immunoblot analyses showed no difference in LV expression levels of PPARalpha or RXRalpha between DSs and DRs. These findings indicate that a nuclear complex of PPARalpha/RXRalpha is present in adult rat LV and is markedly downregulated in the hypertrophied LV from DS rats, which may account for the loss of transcriptional activation. The downregulation of this complex precedes LV systolic dysfunction and is mediated at the posttranslational levels.
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PMID:A nuclear complex containing PPARalpha/RXRalpha is markedly downregulated in the hypertrophied rat left ventricular myocardium with normal systolic function. 1147 59

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that include PPAR-alpha, PPAR-gamma, and PPAR-delta. We hypothesized that PPAR expression in blood vessels could be reduced in hypertension to result in increased vascular growth and reduced apoptosis. We investigated the abundance of PPAR-alpha and PPAR-gamma in aorta and mesenteric arteries from young (6-week-old) and adult (16-week-old) spontaneously hypertensive rats (SHR) compared with age-matched control Wistar-Kyoto rats (WKY). mRNA levels of PPAR-alpha and PPAR-gamma were determined by reverse transcription-polymerase chain reaction. Protein expression was evaluated by Western blot and by immunohistochemistry. PPAR-gamma was expressed in aortic and mesenteric vascular smooth muscle cells (VSMCs) from intact tissue and cultured cells. PPAR-alpha was expressed in intact vascular tissue but was almost undetectable in cultured VSMCs. In mesenteric arteries from adult SHR, PPAR-alpha and PPAR-gamma mRNA levels were significantly greater than in WKY (P<0.05). In aorta, PPAR-alpha mRNA was significantly (P<0.05) more abundant in adult (but not in young) SHR than in WKY, whereas there was no difference in PPAR-gamma mRNA between WKY and SHR. PPAR-alpha and PPAR-gamma mRNA were greater in mesenteric arteries (P<0.05) in young and adult SHR than in WKY. Expression of PPAR-alpha and PPAR-gamma was similar in SHR and WKY in other tissues. In cultured mesenteric VSMCs, PPAR-gamma mRNA was 3-fold higher in SHR than in WKY. Immunohistochemistry demonstrated that PPAR-gamma resided constitutively in the cytoplasm in primary and low-passaged aortic and mesenteric VSMCs, whereas PPAR-alpha was almost undetectable. Thus, aorta and mesenteric resistance arteries from SHR in the prehypertensive and the established phase of hypertension exhibit increased expression of both PPAR isoforms, whereas other tissues do not. Changes (increases) in PPAR expression may play a compensatory role in the remodeling of blood vessels in SHR.
Hypertension 2001 Aug
PMID:Increased expression of peroxisome proliferator-activated receptor-alpha and -gamma in blood vessels of spontaneously hypertensive rats. 1150 85

Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.
Hypertension 2002 Nov
PMID:Antiinflammatory and antiarteriosclerotic effects of pioglitazone. 1241 63

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1/PGC-1) is a transcriptional coactivator of nuclear hormone receptors implicated in blood pressure regulation. We therefore ascertained whether the PPARGC1 gene locus is associated with hypertension. We studied associations of 3 polymorphisms in PPARGC1 transcripts with hypertension in 683 middle-aged men and 530 middle-aged women of a cross-sectional Austrian population. Hypertension was defined by average values of systolic or diastolic ambulatory blood pressure readings (taken between 7 AM and 10 PM) above 140 and/or 90 and/or use of antihypertensive medication. Among the 3 polymorphic sites, genotype distributions associated with Gly482Ser differed by hypertension status in men (P=0.0038), but not in women. The less common Ser482 allele was associated with a modest, but significant, reduction in the prevalence of hypertension in men. The distribution of 3 loci haplotypes also differed in men with and without hypertension (P=0.015). Despite its moderate effect, but because of its high frequency (approximately 64%), the more common risk allele contributed to hypertension in 35% (95% CI 16% to 54%) of our male population. These results suggest, but do not prove, that PPARGC1 participates in blood pressure control, and sequence substitutions at its gene locus confer an increased risk of hypertension to a substantial proportion of men.
Hypertension 2003 Feb
PMID:Peroxisome proliferator-activated receptor-gamma coactivator-1 gene locus: associations with hypertension in middle-aged men. 1257 9

Peroxisome proliferator-activated receptor (PPAR) activation may prevent cardiac hypertrophy and inhibit production of endothelin-1 (ET-1), a hypertrophic agent. The aim of this in vivo study was to investigate the effects of PPAR activators on cardiac remodeling in DOCA-salt rats, a model overexpressing ET-1. Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were randomly divided into 4 groups: control rats, DOCA-salt, DOCA-salt+rosiglitazone (PPAR-gamma activator, 5 mg/kg per day), and DOCA-salt+fenofibrate (PPAR-alpha activator, 100 mg/kg per day). After 3 weeks of treatment, mean arterial blood pressure was significantly increased in DOCA-salt by 36 mm Hg. Mean arterial blood pressure was normalized by coadministration of rosiglitazone but not by fenofibrate. Both PPAR activators prevented cardiac fibrosis and abrogated the increase in prepro-ET-1 mRNA content in the left ventricle of DOCA-salt rats. Coadministration of rosiglitazone or fenofibrate failed to prevent thickening of left ventricle (LV) walls as measured by echocardiography and the increase in atrial natriuretic peptide mRNA levels. However, rosiglitazone and fenofibrate prevented the decrease in LV internal diameter and thus concentric remodeling of the LV found in DOCA-salt rats. Taken together, these data indicate a modulatory role of PPAR activators on cardiac remodeling in mineralocorticoid-induced hypertension, in part associated with decreased ET-1 production.
Hypertension 2003 Oct
PMID:Peroxisome proliferator-activated receptor-alpha and receptor-gamma activators prevent cardiac fibrosis in mineralocorticoid-dependent hypertension. 1286 Aug 36

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate the expression of target genes. Three types of PPAR have been identified: PPAR alpha, PPAR beta/delta and PPAR gamma. The known endogenous PPAR ligands are polyunsaturated fatty acids and eicosanoids, such as 15-deoxy-delta 12,14-prostaglandin J2 and leukotriene B4. Two classes of drugs, fibrates and thiazolidinediones, bind to PPAR alpha and PPAR gamma, respectively. PPARs are involved in the regulation of the lipid metabolism and adipogenesis but are also expressed in the vasculature. PPARs activators inhibit inflammatory reactions within the vascular wall, inhibit vascular smooth muscle cells migration and proliferation and affect foam cells formation by changing the expression of scavenger receptors. PPAR agonists lower blood pressure and improve endothelial function in different animal models of hypertension as well as in humans. PPAR gamma ligands inhibit the development of atherosclerosis in LDL receptor deficient and apolipoprotein E deficient mice and in diabetic humans. PPAR gamma agonists have also been shown to attenuate myocardial hypertrophy and protect against ischemia-reperfuion injury.
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PMID:[Peroxisome proliferator-activated receptors (PPAR) in pathophysiology of the circulatory system and prospective use of agonists of these receptors in therapy]. 1286 56

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPARgamma is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPARgamma in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) increased promoter activity, whereas cotransfection of a dominant negative PPARgamma inhibited it. To determine the role of 15dPGJ2 in expression of proinflammatory genes, we tested its effect on interleukin-1beta induction of cyclooxygenase-2 (COX-2). 15dPGJ2 decreased interleukin-1beta stimulation of COX-2 by 40% and PGE2 production by 73%. We next questioned whether 15dPGJ2 was modulating the expression of inducible prostaglandin E2 synthase (PGES) and found that it completely blocked interleukin-1beta induction of PGES. Use of a second PPARgamma agonist, troglitazone, and the selective PPARgamma antagonist GW9662 demonstrated that the effects seen were PPARgamma-dependent. In addition, we found that 15dPGJ2 blocked interleukin-1beta stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ2 may play an anti-inflammatory role in a PPARgamma-dependent manner, decreasing COX-2, PGES, and PGE2 production, as well as iNOS expression.
Hypertension 2003 Oct
PMID:PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. 1288 95


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