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

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.
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PMID:A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms. 1566 58

Metabolic syndrome (MS), a condition characterized by multiple related clinical disorders including insulin resistance, central obesity, hyperlipidemia, hypertension, and heart disease, is an increasingly prevalent disease in industrialized societies. The intense research interest in the peroxisome proliferator-activated receptors (PPARs), by both the pharmaceutical industry and academia, stems largely from the well-documented therapeutic actions of their synthetic agonists in alleviating several of the maladies associated with MS. This report focuses on the current understanding of the mechanisms of action of PPAR agents and their clinical use in the context of MS.
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PMID:PPAR ligands: potential therapies for metabolic syndrome. 1566 17

The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.
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PMID:PPARs: molecular targets in the pharmacogenomics era. 1578 50

To investigate whether variations in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) are associated with essential hypertension and type 2 diabetes in a Chinese population. A case-control study design was applied in a Chinese population. Two single nucleotide polymorphisms (SNPs), +1302G>A and G482S, in the PGC-1alpha gene were genotyped and compared between 494 unrelated Chinese subjects with essential hypertension and type 2 diabetes and 555 normal control subjects with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. These two polymorphisms were in highly significant linkage disequilibrium with each other (p <0.0001). The frequency of the 482S allele was 42.9% in the Chinese population, which was similar to the frequency in the Japanese population (43.7%), but much higher than those of Caucasian populations (30.8% to 38.1%). There were no associations of the G482S and +1302G>A polymorphisms and haplotype combinations with essential hypertension and type 2 diabetes. In addition, no associations were found between these two polymorphisms and blood pressure. In conclusion, these results indicated that these two variations in the PGC-1alpha gene might not contribute to the risk of hypertension and type 2 diabetes in the Chinese population studied here.
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PMID:Peroxisome proliferator-activated receptor-gamma coactivator-1alpha polymorphism is not associated with essential hypertension and type 2 diabetes mellitus in Chinese population. 1582 63

Hypertension is a very common comorbidity in patients with Cushing's disease/syndrome, resulting from the interplay of several pathophysiologic mechanisms, including stimulation of mineralocorticoid and glucocorticoid receptors as well as the associated insulin resistance, sleep apnea, and overexpression of renin-angiotensin system. Although treatment of Cushing's disease results in resolution or amelioration of hypertension in these patients, a significant proportion of patients do not achieve complete cure or require a prolonged period of time for complete response to therapy. Therefore, therapeutic strategies for Cushing's-specific hypertension are necessary to decrease morbidity and mortality associated with this disease. In this review, we discuss the pathophysiology of hypertension in patients with Cushing's disease, highlighting the therapeutic options, including the exciting new developments in the role of peroxisome proliferator-activated receptor (PPAR)-g agonists in the management of this patient population.
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PMID:Hypertension in patients with Cushing's disease: pathophysiology, diagnosis, and management. 1591 97

The metabolic syndrome is defined as a condition characterized by a set of clinical criteria: insulin resistance, visceral obesity, atherogenic dyslipidemia, and hypertension. The major risk factors leading to the epidemic of this syndrome in the United States are visceral obesity, physical inactivity, and an atherogenic diet. The available current evidence suggests that the first step in management of patients with metabolic syndrome should be focused on lifestyle modifications (eg, weight loss and physical activity). The treatment should be based on two major components: behavioral change to reduce caloric intake and an increase in physical activity. A realistic goal for weight reduction should be 7% to 10% over 6 to 12 months. The general dietary recommendations include low intake of saturated fats, trans fats and cholesterol, and diets with low glycemic index. Soy protein could be more beneficial than animal protein in weight reduction and correction of dyslipidemia. Physical activity is associated with successful weight reduction and these therapeutic lifestyle changes can reduce by half the progression to new-onset diabetes in patients with metabolic syndrome. Physical activity recommendations should include practical, regular, and moderated regimens of exercise, with a daily minimum of 30 to 60 minutes. An equal balance between aerobic exercise and strength training is advised. Medication therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. There is no single best therapy and the treatment should consist of treatment of individual component(s). Atherogenic dyslipidemia should be controlled with statins if there is concomitant increase in low-density lipoprotein cholesterol and if indicated with combination therapy, including fibrates, nicotinic acid, bile acid-binding resins, or ezetimibe. Drugs such as thiazolidinediones and renin-angiotensin system blockers are a few of the available agents in this category. Some evidence suggests that angiotensin-converting enzyme inhibitors and b blockers are more beneficial for treatment of hypertension in patients with metabolic syndrome. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor agonists, will broaden the horizons of the current treatment options in metabolic syndrome.
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PMID:Current Treatment Options for the Metabolic Syndrome. 1591 5

The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR)gamma. Telmisartan also stimulated adiponectin protein expression, whereas the non-PPARgamma-activating ARB eprosartan had no effect. Blockade of PPARgamma activation by the PPARgamma antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPARgamma activation involving a post-transcriptional mechanism.
Hypertension 2005 Jul
PMID:PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. 1593 9

Endothelin B (ETB) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ETB receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) clofibrate in drinking water (80 mg per day), (2) ETB receptor antagonist A-192621 in food (10 mg/kg per day), or (3) clofibrate and A-192621. During ETB receptor blockade, clofibrate had no effect on mean arterial pressure (MAP) under normal salt conditions. In contrast, clofibrate significantly inhibited the increase in MAP produced by A-192621 in rats fed a high-salt diet (34+/-3 versus 19+/-4 mm Hg; P <0.05). Similar results were observed in female rats administered A-192621 and fed a high-salt diet. ETB receptor blockade significantly decreased CYP4A protein expression in the renal cortex of rats on high salt. Clofibrate significantly increased renal cortical and medullary CYP4A protein expression in A-192621-treated male rats on high salt. Therefore, chronic PPAR-alpha agonist treatment reduces salt-dependent hypertension produced by ETB receptor blockade in male and female Sprague-Dawley rats. This suggests a possible relationship between ETB receptor activation and the maintenance of CYP4A protein expression in the kidney of rats fed a high-salt diet.
Hypertension 2005 Aug
PMID:Peroxisome proliferator-activated receptor-alpha activation reduces salt-dependent hypertension during chronic endothelin B receptor blockade. 1596 65

The metabolic syndrome leads to cardiovascular disease and type 2 diabetes mellitus, through multiple risks, such as insulin resistance, dyslipidemia, hyperinsulinemia, and hypertension. It also represents a disorder of partial genetic background as mutations of the peroxisome proliferator-activated receptor-gamma (PPAR-g). Thiazolidinedione agonists for the PPAR-g system are effective in control of insulin resistance and diabetes. Telmisartan has a molecular structure that imparts partial agonist properties with the PPAR-g molecule, which results in reductions in glucose and lipid metabolism. Administration of telmisartan to rats on a high-fat, high-carbohydrate diet leads to reductions in glucose, insulin, and triglyceride levels. The results imply that the ARB agent, telmisartan, could treat both the hemodynamic and metabolic aberrations seen in subjects with the metabolic syndrome, such as insulin resistance, glucose intolerance, and hypertension.
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PMID:Angiotensin-receptor blocking agents and the peroxisome proliferator-activated receptor-gamma system. 1606 Oct 40

Accumulation of interstitial collagen (fibrosis) between the endothelium and myocytes is one of the hallmarks of cardiac failure in renovascular hypertension (RVH). Renal insufficiency increases plasma homocysteine (Hcy), and levels of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are inversely related to plasma Hcy levels. We hypothesize that in RVH, accumulation of collagen between the endothelium and myocytes leads to endothelial-myocyte disconnection and uncoupling, in part, by hyperhomocysteinemia. Furthermore, we hypothesize that Hcy increases reactive oxygen species, generates nitrotyrosine, activates latent matrix metalloproteinase, and decreases the levels of endothelial nitric oxide in response to antagonizing PPAR-gamma. To create RVH in mice, the left renal artery was clipped with 0.4-mm silver wire for the 2 kidney, 1 clip (2K1C) method. Sham surgery was used as a control. To induce PPAR-gamma, 8 microg/mL ciglitazone (CZ) was administered to drinking water 2 days before surgery and continued for 4 weeks. Mice were grouped as 2K1C, sham, 2K1C+CZ, or sham+CZ (n = 6 in each group). Plasma Hcy increased 2-fold in the 2K1C-treated group (p < 0.05) as compared with the sham, and CZ had no effect on Hcy levels as compared to the 2K1C-treated group. Hcy binding in cardiac tissue homogenates decreased in the 2K1C-treated group but was substantially higher in the CZ-treated group. Cardiac reactive oxygen species levels were increased and endothelial nitric oxide were decreased in the 2K1C-treated group. Matrix metalloproteinase-2 and -9 activities were increased in the 2K1C-treated group compared with the control. Levels of cardiac inhibitor of metalloproteinase were decreased, whereas there was no change in tissue inhibitor of metalloproteinase-1 expression in the 2K1C-treated group vs. the sham-treated group. Collagen and nitrotyrosine levels were increased in the 2K1C-treated group, but mice treated with CZ showed lower levels comparatively. Cardiac transferase deoxyuridine nick-end labeling-positive cells were increased, and muscle cells were impaired in the 2K1C-treated mice vs. the sham-control mice. This was associated with decreased acetylcholine and bradykinin responses, which suggests endothelial-myocyte uncoupling in 2K1C-treated mice. Our results suggest that fibrosis between the endothelium and myocytes leads to an endothelial-myocyte disconnection and uncoupling by Hcy accumulation secondary to increased reactive oxygen species, nitrotyrosine, matrix metalloproteinase, and decreased endothelial nitric oxide in response to antagonizing PPAR-gamma.
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PMID:Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model. 1609 84


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