UMLS:C0020538 - FACTA Search

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

Cardiovascular diseases (CVD) remain the leading cause of mortality in the western societies. Several risk factors predispose to CVD including diabetes, obesity, insulin resistance, dyslipidemia and hypertension. Various pharmacological therapies have been developed to control the risk factors associated to CVD. Fibrates are able to correct dyslipidemia, therefore decreasing CVD risk. Thiazolidinediones (TZD) or glitazones by increasing insulin sensitivity decrease plasma glucose levels in diabetic patients. Both fibrates and TZD activate the peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that play a central role in the control of lipid and glucose metabolism. In this review, we will discuss the mode of action of fibrates and TZD and we will present an overview on PPAR ligands under development.
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PMID:[Pharmacology of PPARalpha, PPARgamma and dual PPARalpha/gamma agonists in clinical development]. 1459 12

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.
Hypertension 2004 May
PMID:Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. 1500 34

Diminished activity of peroxisome proliferator-activated receptor-gamma (PPARgamma) may play a role in the pathogenesis of hypertension and vascular dysfunction. To better understand what genes are regulated by PPARgamma, an experimental data set was generated by microarray analysis, in duplicate, of pooled aortic mRNA isolated from mice treated for 21 days with a PPARgamma agonist (rosiglitazone) or vehicle. Of the 12,488 probe sets present on the array (Affymetrix MG-U74Av2), 181 were differentially expressed between groups according to a statistical metric generated using Affymetrix software. A significant correlation was observed between the microarray results and real-time RT-PCR analysis of 39 of these genes. Cluster analysis revealed 3 expression patterns, 29 transcripts of moderate abundance that were decreased (-93%) to very low levels, 106 transcripts that were downregulated (-42%), and 46 transcripts that were upregulated (+70%). Functional groups that were decreased included inflammatory response (-93%, n = 6), immune response (-86%, n = 7), and cytokines (-82%, n = 7). There was an overall upregulation in the oxidoreductase activity group (+47%, n = 9). Individually, six transcripts in this group were increased (+72%), and three were decreased (-34%). Fourteen of the genes map to regions in the rat genome that have been linked to increased blood pressure, and of 142 upstream regions analyzed, sequences resembling the DNA binding site for PPARgamma were identified in 101 of the differentially expressed genes.
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PMID:Gene expression profiling of potential PPARgamma target genes in mouse aorta. 1505 41

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
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PMID:Analysis of candidate genes in Polish families with obesity. 1520 83

Prostaglandins (PGs) of the J2 family including PGJ2, delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2 (15d-PGJ2) are naturally occurring metabolites of PGD2. Among them, 15d-PGJ2 is a powerful ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). 15d-PGJ2 and synthetic PPARgamma ligands have been reported to exert several effects on vascular cells, such as anti-proliferative, differentiation-inducing, anti-apoptotic, and anti-inflammatory effects, most of which seem to be atheroprotective, although PPARgamma-independent mechanisms may be involved. Vascular endothelial cells, intimal smooth muscle cells, and cardiomyocytes express lipocalin-type PGD synthase (L-PGDS) in vivo, which catalyzes the isomeric conversion of PGH2 to PGD2. L-PGDS expression in endothelial cells is stimulated by laminar fluid shear stress. PGD2 and 15d-PGJ2 are detected in the culture medium of endothelial cells exposed to shear stress. Serum and urinary levels of L-PGDS increase in diseases with vascular injuries, such as hypertension and diabetes. Based on these findings, we hypothesize that PGs of the J2 series are physiological substances produced in the vascular wall to protect vascular cells from injurious stimuli and to repress inflammatory reactions. If this hypothesis is correct, PGJ2 family members or other similar substances may provide novel preventive and therapeutic strategies for the treatment of vascular diseases.
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PMID:Prostaglandin J2 family and the cardiovascular system. 1532 May 11

Having previously demonstrated that glucose transporter-4 (GLUT4) expression was reduced in aortas and carotid arteries of deoxycorticosterone acetate (DOCA) salt-hypertensive rats, we hypothesized that troglitazone (TG), through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), would stabilize GLUT4 expression and possibly preserve the differentiated phenotype in vascular smooth muscle cells. In DOCA salt-hypertensive rats treated with TG (100 mg/day), there was a significant (P < 0.001) decrease in systolic blood pressure (BP; 149.9 +/- 4.4 mmHg) compared with the untreated DOCA salt-hypertensive rats (202.2 +/- 10.34 mmHg). Separate trials with rosiglitazone (RS; 3 mg/day) demonstrated a significant (P < 0.001) decrease in BP (DOCA salt, 164.2 +/- 9.8 vs. DOCA-RS, 124.9 +/- 3.7 mmHg) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain SM2 was significantly decreased in aortas of DOCA salt-hypertensive rats and was reversed by TG to levels similar to those in aortas of sham-treated rats. TG (50 microM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats, and the endogenous PPAR-gamma ligand 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2); 20 microM) and TG (50 microM) similarly increased GLUT4, h-caldesmon, and SM2 protein expression in explanted aortas. The expression of activated, phosphorylated Akt was increased by PGJ(2) and TG with no significant effect on total Akt levels. Inhibition of phosphorylated Akt expression using the phosphatidylinositol 3-kinase inhibitor LY-294002 (16 microM) abrogated the increased expression of h-caldesmon and SM2. These data demonstrate that PPAR-gamma agonists maintain or induce expression of markers of the contractile phenotype independently of their effects on hypertension, and that this effect may be mediated through activation of phosphatidylinositol 3-kinase/Akt.
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PMID:Effects of PPAR-gamma ligands on vascular smooth muscle marker expression in hypertensive and normal arteries. 1534 87

Obesity is a common and serious metabolic disorder in the developed world that is occasionally accompanied by type II diabetes, atherosclerosis, hypertension, and hyperlipidemia. We have found that mesoderm-specific transcript (Mest)/paternally expressed gene 1 (Peg1) gene expression was markedly enhanced in white adipose tissue of mice with diet-induced and genetically caused obesity/diabetes but not with streptozotocin-induced diabetes, which does not cause obesity. Administration of pioglitazone, a drug for type II diabetes and activator of peroxisome proliferator-activated receptor (PPAR)gamma, in obese db/db mice reduced the enhanced expression of Mest mRNA in adipose tissue, concomitant with an increase in body weight and a decrease in the size of adipose cells. Ectopic expression of Mest in 3T3-L1 cells caused increased gene expression of adipose markers such as PPARgamma, CCAAT/enhancer binding protein (C/EBP)alpha, and adipocyte fatty acid binding protein (aP)2. In transgenic mice overexpressing Mest in adipose tissue, enhanced expression of the adipose genes was observed. Moreover, adipocytes were markedly enlarged in the transgenic mice. Thus Mest appears to enlarge adipocytes and could be a novel marker of the size of adipocytes.
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PMID:Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. 1535 8

The antihypertensive effect of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone has been reported in patients with diabetes or obesity. The correlation of PPARgamma expression with blood pressure and the therapeutic application of rosiglitazone in spontaneously hypertensive rats (SHR) were investigated in the present study. Systolic blood pressure of 21-week SHR was significantly higher than that of age-matched Wistar-Kyoto rats (WKY) (225 +/- 5 v 144 +/- 2 mm Hg, P <.05). Basal expression levels of PPARgamma proteins in vascular tissues of 21-week SHR were significantly lower than that of age-matched 21-week WKY (P <.05). This reduced expression of PPARgamma was not detected between 5- and 13- week SHR and age-matched WKY. Cardiac PPARgamma expression was also not different among different age groups between SHR and WKY. Chronic treatment with rosiglitazone, but not PPARalpha agonist Wy14643, significantly retarded hypertension development and reversed abnormally faster heart rate in young SHR. An unfavorable effect of rosiglitazone treatment was the increased heart-to-body weight ratio accompanied by left ventricular hypertrophy. In conclusion, vascular PPARgamma protein expression in adult SHR (21 weeks) is significantly decreased in comparison with the age-matched WKY. Chronic rosiglitazone treatment retards hypertension development, but the associated prohypertrophy effect calls for a cautious use of this thiazolidinedindione in the treatment of insulin resistance syndrome associated with hypertension.
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PMID:Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats. 1536 15

Obesity frequently promotes a variety of cardiovascular diseases including atherosclerosis, hypertension, and type 2 diabetes. In a view of both the preventive and therapeutic aspects of the abovementioned diseases, most intensive clinical interventions have been primarily directed at decreasing excessive amounts of fat tissue by a change in the balance between intake and expenditure of energy; such changes are typically effected via daily exercise and diet control. Mechanical stimuli such as stretching and rubbing of fat tissues using gymnastic exercises or massage are believed to decrease obesity; however, there is no report concerning the direct effect of the mechanical stimulation on adipocytes. Here, we demonstrated that cyclic stretch inhibited adipocyte differentiation of mouse 3T3-L1 cells, which was attributable to a reduced expression of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)gamma(2) via the activation of an extracellular signal-regulated protein kinase (ERK) pathway. The inhibitory effect of the cyclic stretching on the differentiation of 3T3-L1 cells could be restored by troglitazone, a synthetic ligand for PPARgamma. Our results provide a molecular basis for the physiological significance of the local application of mechanical stimuli to fat tissues, which is totally independent of a mechanism for systemic energy consumption.
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PMID:[Mechanical stretching inhibits adipocyte differentiation of 3T3-L1 cells: the molecular mechanism and pharmacological regulation]. 1550 99

The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. Indeed, hypertension occurs approximately twice as frequently in patients with diabetes compared with in non-diabetic controls. Conversely, hypertensive patients are more likely than normotensive persons to develop diabetes. In addition, up to 75% of CVD in diabetic patients can be attributed to hypertension. Therefore, the primary goals of treating hypertensive patients with insulin resistance are prevention of type 2 diabetes and cardiovascular events. Then, what is the optimal anti-hypertensive approach to target organ protection in these patients? Several clinical trials suggest that the renin-angiotensin system (RAS) plays a pivotal role in the pathogensis of insulin resistance and CVD in diabetes. Interruption of the RAS with angiotensin-coverting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been shown to prevent the onset of diabetes in hypertensive patients and to reduce cardiovascular and renal disease progression in diabetic patients with hypertension. However, whether we should recommend ARBs for insulin resistant-hypertensive patients or type 2 diabetic patients without nephropathy due to its insulin-sensitizing property remains to be clarified. Recently, telmisartan, an ARB, was found to act as a patrtial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma influences the gene expression involved in carbohydrate metabolism, and pioglitazone and rosiglitazone, ligands for PPAR-gamma, improve insulin resistance in diabetic patients. Furthermore, there is a growing body of evidence that activators of PPAR-gamma exert anti-inflammatory, anti-oxidative and anti-proliferative effects on vascular wall cells, thus decreasing the risks for atherosclerosis. We hypothesize here that due to its unique PPAR-gamma-modulating activity, telmisartan will become a promising 'cardiometabolic sartan', that targets both diabetes and CVD in hypertensive patients. In this paper, we would like to propose the possible ways of testing our hypothesis. Does telmisartan reduce the development of diabetes and CVD in insulin resistant patients pretreated with maximal doses of other ARBs? Does co-treatment with an activator of PPAR-gamma attenuate the effects of telmisartan in these patients? These clinical studies will provide further information whether the beneficial cardiometabolic actions of telmisartan could be ascribed to its PPAR-gamma-inducing property.
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PMID:Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property. 1561 52

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