Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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) 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

It is remarkable that phytoplankton and zooplankton have been producing vitamin D for more than 500 million years. The role of vitamin D in lower non-vertebrate life forms is not well understood. However, it is critically important that most vertebrates obtain an adequate source of vitamin D, either from exposure to sunlight or from their diet, in order to develop and maintain a healthy mineralized skeleton. Vitamin D deficiency is an unrecognized epidemic in most adults who are not exposed to adequate sunlight. This can precipitate and exacerbate osteoporosis and cause the painful bone disease osteomalacia. Once vitamin D is absorbed from the diet or made in the skin by the action of sunlight, it is metabolized in the liver to 25-hydroxyvitamin D [25(OH)D] and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D interacts with its nuclear receptor (VDR) in the intestine and bone in order to maintain calcium homeostasis. The VDR is also present in a wide variety of other tissues. 1,25(OH)2D interacts with these receptors to have a multitude of important physiological effects. In addition, it is now recognized that many tissues, including colon, breast and prostate, have the enzymatic machinery to produce 1,25(OH)2D. The insights into the new biological functions of 1,25(OH)2D in regulating cell growth, modulating the immune system and modulating the renin-angiotensin system provides an explanation for why diminished sun exposure at higher latitudes is associated with increased risk of dying of many common cancers, developing type 1 diabetes and multiple sclerosis, and having a higher incidence of hypertension. Another calciotropic hormone that is also produced in the skin, parathyroid hormone-related peptide, is also a potent inhibitor of squamous cell proliferation. The use of agonists and antagonists for PTHrP has important clinical applications for the prevention and treatment of skin diseases and disorders of hair growth.
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PMID:Evolution and function of vitamin D. 1289 11

PPAR (peroxisome-proliferator-activated receptor) is a nuclear receptor. Activation of PPARgamma by its ligands could modulate gene transcription, thereby leading to multiple anti-atherogenic and fibrinolytic effects. However, the association between the 161T allele in exon 6 of the PPARgamma gene and premature AMI (acute myocardial infarction) is not clear. We recruited 146 patients with premature AMI (onset age < or =50 years) and 146 controls. The C161T polymorphism was examined using PCR and restriction-fragment-length polymorphism. Plasma levels of Ab-ox-LDL (antibody against oxidized low-density lipoprotein) were measured in 27 male smokers, whose genotypes have been identified. The frequency of the PPARgamma TT genotype among patients with AMI was significantly higher than that in controls [13% compared with 5.5%; OR (95% CI) 2.7, (1.1-6.5), where OR and CI are odds ratio and confidence interval respectively]. This association was not observed in CC or CT genotypes. Using multivariate logistic regression analyses, we found that the homozygous TT genotype [OR (95% CI), 3.1 (1.2-7.9)], smoking [OR (95% CI), 3.5, (2.1-6.0)], hypertension [OR (95% CI), 3.6, (1.9-6.9)] and diabetes mellitus [OR (95% CI), 3.5 (1.5-8.4)] were independent risk factors for premature AMI. Plasma levels of Ab-ox-LDL were significantly higher in healthy volunteers with the TT genotype compared with those with the CC genotype (49.3+/-18.1 compared with 24.2+/-15.2 units/l respectively; P=0.02). Therefore in our study we observed an association between the PPARgamma 161 TT genotype and premature AMI. Lipid peroxidation was significantly influenced by the 161T allele.
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PMID:The 161TT genotype in the exon 6 of the peroxisome-proliferator-activated receptor gamma gene is associated with premature acute myocardial infarction and increased lipid peroxidation in habitual heavy smokers. 1521 50

The metabolic reduction of 11-keto groups in glucocorticoid steroids such as cortisone leads to the nuclear receptor ligand cortisol. This conversion is an example of pre-receptor regulation and constitutes a novel pharmacological target for the treatment of metabolic disorders such as insulin resistance and possibly other derangements observed in the metabolic syndrome, such as hyperlipidemia, hypertension, and lowered insulin secretion. This reaction is carried out by the NADPH-dependent type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1), an enzyme attached through an integral N-terminal transmembrane helix to the lipid bilayer and located with its active site within the lumen of the endoplasmic reticulum. Here we report the crystal structure of recombinant guinea pig 11beta-HSD1. This variant was determined in complex with NADP at 2.5 A resolution and crystallized in the presence of detergent and guanidinium hydrochloride. The overall structure of guinea pig 11beta-HSD1 shows a clear relationship to other members of the superfamily of short-chain dehydrogenases/reductases but harbors a unique C-terminal helical segment that fulfills three essential functions and accordingly is involved in subunit interactions, contributes to active site architecture, and is necessary for lipid-membrane interactions. The structure provides a model for enzyme-lipid bilayer interactions and suggests a funneling of lipophilic substrates such as steroid hormones from the hydrophobic membrane environment to the enzyme active site.
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PMID:The crystal structure of guinea pig 11beta-hydroxysteroid dehydrogenase type 1 provides a model for enzyme-lipid bilayer interactions. 1554 90

Hypertension commonly occurs as part of a genetically complex disorder of carbohydrate and lipid metabolism known as the metabolic syndrome. Most current antihypertensive drugs appear ineffective against the metabolic syndrome, which is a strong predictor of cardiovascular disease and death in affected patients. Angiotensin II can influence the activity of certain genes and cellular and biochemical pathways that may contribute to the pathogenesis of the metabolic syndrome. However, as a class, angiotensin II receptor blockers (ARBs) have proven only minimally to modestly effective in ameliorating the disturbances in carbohydrate and lipid metabolism that characterise the metabolic syndrome. Recent preclinical studies indicate that the ARB telmisartan acts as a selective peroxisome proliferators-activated receptor-gamma (PPARgamma) modulator when tested at concentrations that might be achievable with oral doses recommended for treatment of hypertension; this property does not appear to be shared by other ARBs. PPARgamma is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and is an attractive therapeutic target for the prevention and control of insulin resistance, type 2 diabetes and atherosclerosis. In cellular transactivation assays, telmisartan functioned as a partial agonist of PPARgamma and achieved 25-30% of maximal receptor activation attained with conventional PPARgamma ligands. Preclinical and clinical studies indicate that administration of telmisartan can improve carbohydrate and lipid metabolism without causing the side effects that accompany full PPARgamma activators. If the preliminary data are supported by the results of ongoing large-scale clinical studies, telmisartan could have a central role in the prevention and treatment of metabolic syndrome, diabetes and atherosclerosis.
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PMID:Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. 1586 21

Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor family, has been implicated in the regulation of vascular smooth muscle cell (VSMC) growth; however, the underlying mechanisms are still not fully understood. We hypothesized that PPAR gamma functional deficiency may contribute to the enhanced proliferation of VSMC associated with hypertension in spontaneously hypertensive rats (SHR). We observed that PPAR gamma mRNA level in SHR VSMC was 3 approximately 4 fold higher than that from Wistar-Kyoto rats (WKY), but the protein expression levels of PPAR gamma are significantly lower in SHR than WKY VSMC, suggesting an impaired control of PPAR gamma protein expression in SHR VSMC. The deficiency of PPAR gamma protein expression in SHR VSMC was demonstrated by PPAR gamma reporter gene assays. Furthermore, the exaggerated growth of SHR VSMC was markedly attenuated by adenoviral PPAR gamma overexpression. Taken together, our results provided the first direct evidence that impaired expression of PPAR gamma protein contributes to the exaggerated growth of SHR VSMC.
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PMID:Impaired expression of PPAR gamma protein contributes to the exaggerated growth of vascular smooth muscle cells in spontaneously hypertensive rats. 1597 Feb 97

Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARalpha agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARgamma agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARalpha and PPARgamma agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARalpha and PPARalpha agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes.
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PMID:Inflammation, dyslipidaemia, diabetes and PPars: pharmacological interest of dual PPARalpha and PPARgamma agonists. 1603 93

Fibric acid is a synthetic ligand of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-alpha that is highly expressed in skeletal muscle and heart, where it promotes beta-oxidation of fatty acids to mediate hypolipidemic actions. PPAR-alpha regulates expression of key proteins involved in atherogenesis, vascular inflammation, plaque instability, and thrombosis. Thus, PPAR-alpha may exert direct antiatherogenic actions in the vascular wall. Endothelial dysfunction associated with the metabolic syndrome and other insulin-resistant states is characterized by impaired insulin-stimulated nitric oxide production from the endothelium and decreased blood flow to skeletal muscle. Thus, improvement in insulin sensitivity leads to improved endothelial function. This may be an additional mechanism whereby fibrates decrease the incidence of coronary heart disease. Adiponectin is a protein secreted specifically by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. In this review, we discuss the mechanisms underlying the vascular and metabolic effects of fibrates that may act synergistically to prevent or regress atherosclerosis and coronary heart disease.
Hypertension 2005 Nov
PMID:Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. 1623 May 15

Cardiovascular diseases are the leading cause of morbidity and mortality in the US. Proper management and/or prevention of atherosclerosis and hypertension, two complex and chronic disorders, would significantly reduce the risk for cardiovascular events such as myocardial infarction and stroke, but this requires an understanding of the mechanisms underlying their development and progression. Whereas a great deal has been learned and applied toward the management of these disorders, especially hypertension, morbidity and mortality remains unacceptably high, most likely because there are disease-causing mechanisms that have yet to be fully recognized. Understanding these disease mechanisms is necessary so that novel management strategies can be developed. One of these novel mechanisms centers on peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a member of the nuclear receptor superfamily of ligand-activated transcription factors known to play a role in glucose homeostasis and adipocyte differentiation and, more recently, has been shown to have anti-inflammatory, antiatherogenic, and antihypertensive effects. Thiazolidinediones, a class of drugs used in the treatment of type 2 diabetes mellitus, are high-affinity ligands for PPAR-gamma. In this review, the anti-inflammatory, anti-atherosclerotic, and anti-hypertensive mechanisms by which PPAR-gamma and its agonists are thought to exert protective effects on the cardiovascular system are discussed. Ongoing clinical trials using PPAR-gamma activators for the management of cardiovascular diseases, especially in patients with type 2 diabetes mellitus, are summarized.
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PMID:Peroxisome proliferator-activated receptor-gamma and its agonists in hypertension and atherosclerosis : mechanisms and clinical implications. 1625 27

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The activation of PPAR-gamma, an isotype of PPARs, can either increase or decrease the transcription of target genes. The genes controlled by this form of PPAR have been shown to encode proteins or peptides that participate in the pathogenesis of insulin resistance. Insulin resistance is defined as a state of reduced responsiveness to normal circulating concentrations of insulin and it often co-exists with central obesity, hypertension, dyslipidemia, and atherosclerosis. There is substantial evidence that links obesity with insulin resistance and type-2 diabetes. The early phase of obesity-related insulin resistance has 2 components: (a) interruption of lipid homeostasis leading to the increased plasma concentration of fatty acids that is normally suppressed by the activation of PPAR-gamma, and (b) activation of factors such as cytokines depressed by PPAR-gamma that cause insulin resistance. Therefore, it is logical to suggest that activation of PPAR-gamma may partially reverse the state of insulin resistance. Evidently, activation of the nuclear receptor, PPAR-gamma, by thiazolidinediones has been reported to ameliorate insulin resistance. Although hepatotoxity and possibility to induce congestive heart failure (CHF) limit the widely use of thiazolodinediones, they are still powerful weapon to fight against insulin resistance and type-2 diabetes if use properly. This article reviews the physiology of PPAR-gamma and insulin-signaling transduction, the pathogenesis of insulin resistance in obesity-related type-2 diabetes, the pharmacological role of PPAR-gamma in insulin resistance, and additional effects of thiazolidinediones.
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PMID:Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance. 1630 9


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