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)

We investigated the effects of troglitazone on cytokine-stimulated nitric oxide (NO) production in cultured rat vascular smooth muscle cells (VSMC). The increase in NO formation caused by interleukin-1alpha (IL-1) was enhanced by troglitazone in a concentration-dependent manner. Bacterial lipopolysaccharide-stimulated NO synthesis was also increased by troglitazone. The combinations of IL-1, tumor necrosis factor-alpha, or lipopolysaccharide with interferon-gamma (IFN) were strong stimuli for induction of NO synthesis in VSMC, which were further potentiated by the presence of troglitazone. When troglitazone was added at increasing intervals after the stimulation of VSMC with IL-1, the enhancement in NO production decreased as the interval lengthened, suggesting that troglitazone alters NO synthase (NOS) expression by VSMC rather than having a direct affect on VSMC NOS activity. Troglitazone had no effect on IL-1-elicited or IL-1/IFN-elicited nuclear factor-kappaB activity in VSMC. Troglitazone inhibited the degradation of cytokine-induced NOS mRNA. Thus troglitazone appears to enhance IL-1-induced NOS mRNA levels by prolonging its half-life rather than activating its transcription, which is nuclear factor -kappaB-dependent. No expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) was detected in VSMC, and 15-deoxy-D12,14 prostaglandin J2, the natural ligand for the PPARgamma, did not resemble the effect of troglitazone on IL-1-induced NO synthesis. These results indicate that troglitazone upregulates cytokine-stimulated NO synthesis in VSMC through PPARgamma-independent mechanisms. Considering its inhibitory effects on the action of numerous growth factors on VSMC, the direct vascular effects of troglitazone shown in this study may have important implications for prevention of restenosis and possibly atherosclerosis.
Hypertension 1999 Apr
PMID:Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells. 1020 28

1. Insulin resistance has been highlighted as a common causal factor for hypertension, hyperlipidaemia, diabetes mellitus and obesity, all of which are recognized to occur simultaneously, and a distinct clinical entity is defined as 'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents, thiazolidinediones (TZD) has been developed and has been shown to improve insulin resistance by binding and activating a nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma. 3. cDNA of rat PPAR gamma 1 and gamma 2 were cloned and gene regulation of PPAR gamma in rat mature adipocytes was examined. Hydrogen peroxide, an oxygen radical, which is recognized to be the common intracellular signal for multiple risk factors, potently down-regulated PPAR gamma mRNA expression in rat mature adipocytes. 4. Tumour necrosis factor (TNF)-alpha, which is considered to play a role in obesity-induced non-insulin-dependent diabetes mellitus and to augment oxidative stress, also suppressed PPAR gamma expression. 5. Thiazolidinediones dose-dependently recovered TNF-alpha-induced down-regulation of PPAR gamma mRNA expression. 6. The modulation of PPAR gamma expression by TZD can be one mechanism for the improvement of insulin resistance by TZD. 7. Vascular tone and remodelling are controlled by several vasoactive autocrine/paracrine factors produced by endothelial cells in response to several vascular injury stimuli, including hypertension. The PPAR gamma gene transcript was detected in cultured endothelial cells. 8. The administration of TZD stimulated the endothelial secretion of type-C natriuretic peptide, which is one of the natriuretic peptide family and is demonstrated by us to act as a novel endothelium-derived relaxing peptide. 9. Concomitantly, TZD significantly suppressed the secretion of endothelin, a potent endothelium-derived vasoconstricting peptide. 10. Thiazolidinediones can affect vascular tone and growth by modulating the production of endothelium-derived vasoactive substances to influence occurrence and progression of hypertension and atherosclerosis.
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PMID:Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. 1040 88

Numerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPAR gamma modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.
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PMID:PPAR gamma and the treatment of insulin resistance. 1104 66

Omega-3 fatty acids (n-3 FAs) have been shown to exert a blood pressure-lowering effect in hypertension, possibly in part by influencing vascular structure. We previously demonstrated that n-3 FAs induce vascular smooth muscle cell (VSMC) apoptosis, which could exert an effect on the structure of blood vessels. In the present study, we investigated signaling pathways through which n-3 FAs mediate apoptosis in VSMCs. Cultured mesenteric VSMCs from Sprague-Dawley rats were stimulated with docosahexaenoic acid (DHA), a representative n-3 FAs. Morphological changes in apoptosis and DNA fragmentation were examined with phase-contrast microscopy and fluorescence microscopy with Hoechst 33342 staining. To clarify possible pathways of apoptosis, we evaluated the expression of phosphorylated p38 mitogen-activated protein kinases, bax, bcl-2, cytochrome c, and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) with Western blot analysis. DHA treatment induced cell shrinkage, cell membrane blebbing, and apoptotic bodies in VSMCs. DHA time-dependently activated p38 mitogen-activated protein kinases, bax, PPAR-alpha, and cytochrome c, with maximal effects obtained after 5 and 30 minutes and 1 and 3 hours, respectively. SB-203580 and SB-202190, selective p38 inhibitors, reduced DHA-elicited apoptosis and expression of PPAR-alpha but had no effect on the expression of bax or cytochrome c. The present results indicate that DHA induces apoptosis in VSMCs through >/=2 distinct mechanisms: (1) a p38-dependent pathway that regulates PPAR-alpha and (2) a p38-independent pathway via dissipation of mitochondrial membrane potential and cytochrome c release. The death-signaling pathway stimulated by DHA may involve an integration of these multiple pathways. By triggering VSMC apoptosis, DHA may play a pathophysiological role in vascular remodeling in cardiovascular disease.
Hypertension 2000 Nov
PMID:Docosahexaenoic acid, a peroxisome proliferator-activated receptor-alpha ligand, induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase. 1108 55

Type 2 diabetes mellitus is a condition associated with an increased risk of coronary artery disease. This condition is currently reaching epidemic proportions in the Western world. Epidemiological studies have shown that insulin resistance and the constellation of metabolic alterations associated with type 2 diabetes mellitus such as dyslipidaemia, systemic hypertension, obesity and hypercoagulability, have an effect on the premature onset and severity of atherosclerosis. Albeit direct, the link between insulin resistance and atherogenesis is rather complex. It is likely that its complexity relates to the interaction between genes that predispose to insulin resistance and genes that independently regulate lipid metabolism, coagulation processes and biological responses of the arterial wall. The rapid development of molecular biology in recent years has resulted in a better understanding of the immune and inflammatory mechanisms that underlie insulin resistance and atherosclerosis. For example, it is known that nuclear transcription factors such as nuclear factor kappa beta and peroxisome proliferator-activated receptor are involved in atherosclerosis. The former modulates gene expression which encodes pro-inflammatory proteins vital for the development of the atheromatous plaque. In the presence of insulin resistance there are multiple activating factors that could explain the early onset and severity of atherosclerosis. Glitazones, the new oral antidiabetic drugs and agonists of peroxisome proliferator-activated receptor, have been shown to improve peripheral insulin sensitivity and to also delay atherosclerosis progression in experimental models. Their beneficial effects have been linked to their anti-inflammatory effect.
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PMID:[Diabetes mellitus, inflammation and coronary atherosclerosis: current and future perspectives]. 1141 81

Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15-deoxy-(Delta)(12,14)-prostaglandin J(2) and thiazolidinediones have been shown to be ligands for peroxisome proliferator-activated receptor (PPAR)-gamma and activate PPAR-gamma. In the present work, we have studied the effect of PPAR-gamma on AT1R expression in rat vascular smooth muscle cells (VSMCs). We observed that: 1) endogenous AT1R expression was significantly decreased by PPAR-gamma ligands both at messenger RNA and protein levels, whereas AT1R messenger RNA stability was not affected; 2) AII-induced increase of (3)H-thymidine incorporation into VSMCs was inhibited by PPAR-gamma ligands; 3) rat AT1R gene promoter activity was significantly suppressed by PPAR-gamma ligands, and PPAR-gamma overexpression further suppressed the promoter activity; 4) transcriptional analyses using AT1R gene promoter mutants revealed that a GC-box-related sequence within the -58/-34 region of the AT1R gene promoter was responsible for the suppression; 5) Sp1 overexpression stimulated AT1R gene transcription via the GC-box-related sequence, which was inhibited by additional PPAR-gamma overexpression; 6) electrophoretic mobility shift assay suggested that Sp1 could bind to the GC-box-related sequence whereas PPAR-gamma could not; 7) antibody supershift experiments using VSMC nuclear extracts revealed that protein-DNA complexes formed on the GC-box-related sequence, which were decreased by PPAR-gamma coincubation, were mostly composed of Sp1; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-gamma and Sp1. Taken together, it is suggested that activated PPAR-gamma suppresses AT1R gene at a transcriptional level by inhibiting Sp1 via a protein-protein interaction. PPAR-gamma ligands, thus, may inhibit AII-induced cell growth and hypertrophy in VSMCs by AT1R expression suppression and possibly be beneficial for treatment of diabetic patients with hypertension and atherosclerosis.
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PMID:Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. 1141 35

Patients with insulin resistance and/or type 2 diabetes have a 5-fold increase in cardiovascular mortality rate. Therefore, it is a current issue of discussion that arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity. Concerning a possible molecular link between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between lipid metabolism, insulin action, and obesity at a gene regulatory level. Alterations in the structure, function and regulation of transcription factors appear to be such signalling steps which might play an essential role in the pathogenesis and therapy of cardiovascular risk factors associated with insulin resistance, eg the so called metabolic syndrome. Recent examples are members of the nuclear hormone receptor superfamily, eg peroxisome proliferator-activated receptor (PPAR) isoforms and sterol regulatory element-binding proteins (SREBPs). Beside their regulation by different metabolites, these transcription factors are also targets of hormones, like insulin and leptin, growth factors, and inflammatory signals. Therefore, they appear to be a point of signalling convergence at a gene regulatory level. Major signalling pathways coupling receptors at the cell surface for hormones, growth factors as well as cytokines to gene regulatory events in the nucleus are the MAP-kinase cascades. We have recently defined different postreceptor defects in these pathways in patients with clinical phenotypes corresponding to congenital lipoatrophy. Therefore, these studies may identify novel pathways which play a role in the control of body weight, insulin sensitivity and cardiovascular risk.
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PMID:Insulin-regulated transcription factors: molecular link between insulin resistance and cardiovascular risk factors. 1146 84

Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.
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PMID:Insulin resistance and insulin sensitizers. 1168 68

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg.kg(-1).day(-1)) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta-oxidation and the enhancement of mitochondrial gene expression.
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PMID:Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha. 1193 85

Type 2 diabetes is characterised by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycaemia may differ due to heterogeneity of the disease. Under most circumstances, insulin resistance is the earliest detectable defect in pre-diabetic individuals but it is not known whether this is the primary defect or secondary to other abnormalities such as abdominal obesity with excessive free fatty acid turnover and increased lipid deposits in muscle. Initially, enhanced insulin secretion can compensate for the insulin resistance but early phase insulin secretion is impaired. In the transition from normal to impaired and diabetic glucose tolerance, insulin sensitivity deteriorates about 40% whereas insulin secretion deteriorates 3-4 fold. In addition to insulin resistance, the metabolic syndrome includes hypertension, dyslipidaemia, obesity and microalbuminuria. In patients with manifest diabetes, chronic hyperglycaemia can result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity). Abdominal obesity and insulin resistance are strongly correlated and studies have aimed at understanding the genetic basis. Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. Therefore, type 2 diabetes is multigenic and appears to represent a collision between thrifty genes and an affluent society. Successful management will require treatments targeted at defects of both insulin secretion and insulin resistance.
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PMID:Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. 1196 29


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