Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

Aim of the study was to investigate association of gene candidate polymorphisms encoding elements of the renin-angiotensin system and participating in regulation of vascular tone with development of microalbuminuria in patients with hypertensive disease. We examined 93 patients (52 women, 41 men, mean age 58.3+/-1.12 years, mean duration of hypertension 15.6+/-1.16 years) with hypertensive disease. Two patients had arterial hypertension (AG) with I, 22 with II, 63 with III degree of blood pressure (BP) elevation. Thirty four patients smoked, 2 had stroke in anamnesis, 33 had ischemic heart disease, in 58 heredity burdened with cardiovascular diseases was noted. In 38 patients hypertrophy of left ventricular myocardium was revealed. As gene-candidates we considered AGT, ACE, AT2R1, CYP11B2, MTHFR, PPARA, PPARG2, NOS3. Patients with microalbuminuria had significantly higher systolic and diastolic BP levels. Groups did not differ significantly according sex, age, disease duration, glucose level. There were no significant differences in involvement of other target organs - hypertrophy of left ventricular myocardium and atherosclerosis of carotid arteries. Patients with microalbuminuria had significantly higher level of blood cholesterol. Patients with and without microalbuminuria differed only in frequencies of genotypes of polymorphic marker A(-153)G of AT2R1 gene. Genotype AA predisposed to development of nephropathy--odds ratio (OR) 4.71 (95CI 1.78-12.97), while genotype AG was protective (OR 0.20 95%CI 0.07 to 0.56, p=0.031). According to results of multifactorial analysis independent factors affecting increase of risk of development of nephropathy in the studied group were level of systolic BP and carriage of genotype AA of polymorphic marker A(-153)G of AT2R1 gene.
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PMID:[Genetic aspects of development of microalbuminuria in patients with hypertensive disease]. 1907 77

Arterial hypertension, insulin resistance, diabetes mellitus are associated with obesity. However exact mechanisms of this association have not been determined yet. Biologically active substances produced by adipose tissue participate in pathogenesis of cardiovascular diseases and complications. In this review we present data on the role of adiponectin -- adipocytokine with unique antiatherogenic, antiinflammatory, and insulin sensitizing properties. Hypoadiponectinemia is considered to be potentially modifiable cardiovascular risk factor and novel therapeutic target. Therapy with PPAR gamma agonists, blockers of renin-angiotensin and sympathetic nervous systems is associated with elevation of concentration of adiponectin.
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PMID:[The role of adiponectin in development and progression of cardiovascular diseases]. 1916 2

The classical view of adipose tissue as a passive reservoir for energy storage is no longer valid. In the past decade, adipose tissue has been shown to have endocrine functions regulating cardiovascular physiology. In the present review we will analyze current knowledge about adiponectin, the most abundant peptide secreted by adipocytes, with particular focus on its cardiovascular actions. Adiponectin secretion is inhibited by TNF-alpha and by catecholamines, and is stimulated by PPAR gamma activation. Adiponectin acts through two main receptors, AdipoR1 and AdipoR2. In the liver, adiponectin modulates lipid and energy metabolism, stimulating fatty acid catabolism and reducing gluconeogenesis. In skeletal muscle, it promotes fatty acid oxidation and glucose uptake. Taken together, the metabolic actions of adiponectin enhance insulin sensitivity and reduce circulating lipid levels. Adiponectin also has a protective effect against atherogenesis, acting on the endothelium and smooth muscle cells, raising NO secretion and inhibiting production of adhesion factors. In the heart, adiponectin inhibits cardiomyocyte hypertrophy and myocardial fibrosis, through poorly understood mechanisms. Adiponectin production has also been shown to be reduced in patients with obesity and type 2 diabetes, and its circulating levels have prognostic significance in various cardiovascular diseases. Finally, the role of this peptide as a therapeutic target has been evaluated, through various lifestyle and pharmacological interventions. Weight loss, physical exercise, renin-angiotensin system inhibitors and PPAR alpha and PPAR gamma agonists enhance adiponectin production. Further studies are needed, however, to clarify the clinical relevance of adiponectin in the pathophysiology and treatment of cardiovascular diseases.
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PMID:Cardiovascular actions of adiponectin: pathophysiologic implications. 1922 10

Aldosterone production causes vascular injury and may occur despite the long-term administration of angiotensin converting enzyme-inhibitors (ACE-I) (ie, aldosterone breakthrough). The angiotensin II receptor blocker (ARB) telmisartan can function as a ligand for peroxisome proliferator-activated receptor (PPAR) gamma. Stimulation of PPAR gamma has been demonstrated to raise adiponectin production and suppress angiotensin II type 1 receptor expression. Thus, we investigated the effect of the ACE-I perindopril erbumin (perindopril) and the ARB telmisartan on plasma levels of aldosterone and adiponectin.Patients with essential hypertension were randomly assigned to receive 48 weeks of perindopril (2-8 mg/d) or telmisartan (20-80 mg/d). We measured adiponectin, aldosterone, angiotensin II, and renin at weeks 0, 8, 24, and 48.A total of 53 subjects were randomized. Data on 51 subjects (25 in the perindopril group and 26 in the telmisartan group; mean age, 65.1 years) were available for analyses. Plasma aldosterone decreased significantly in both the telmisartan (69.9+/-5.6 to 58.1+/-5.4 pg/mL) and perindopril (74.1+/-4.7 to 64.7+/-5.3 pg/mL) groups at 8 weeks, but returned toward the baseline in the perindopril group (67.9+/-4.1 pg/mL) at 24 weeks. Plasma glycated hemoglobin levels or urine albumin did not change significantly after the treatment in either group.Telmisartan seemed to be more effective at suppressing aldosterone and raising adiponectin levels than perindopril; however, improvements in insulin sensitivity and albuminuria were not detected. These results are consistent with the idea that the use of an ARB with PPAR gamma stimulating activity is equivalent to ACE-I for the treatment of hypertension.
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PMID:Effects of ARB or ACE-inhibitor administration on plasma levels of aldosterone and adiponectin in hypertension. 1960 54

Vascular fibrosis, characterized by reduced lumen diameter and arterial wall thickening attributable to excessive deposition of extracellular matrix (ECM), links with many clinical diseases and pathological progresses including atherosclerosis. It involves proliferation of vascular smooth muscle cell (VSMC), accumulation of ECM and inhibition of matrix degradation. The risk factors associated with cardiovascular disease, including hypertension, hyperglycemia, dyslipidemia and hyperhomocysteinemia (HHcy), are also suggested as initiation and progression factors of vascular fibrosis. Vascular fibrosis has been found to relate to renin-angiotensin-aldosterone system (RAAS), oxidative stress, inflammatory factors, growth factors and imbalance of endothelium-derived cytokine secretion. Angiotensin II (Ang II) and aldosterone, the circulating effector hormones of RAAS, are recognized as responsible for the pathophysiology of vascular fibrosis. Transforming growth factor-beta (TGF-beta) plays a critical role in ECM accumulation and vascular remodeling via up-regulating the production of several agents including connective tissue growth factor (CTGF) and fibroblast growth factor. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) results in collagen accumulation and adverse matrix remodeling. Aberrant expression or function of peroxisome proliferator-activated receptor gamma (PPAR gamma) is also associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. In this review, we discuss the pathogenesis of vascular fibrosis in atherosclerosis with focus on the networking among main responsible mediators. The main pathophysiologic factors leading to vascular fibrosis will also be discussed.
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PMID:Vascular fibrosis in atherosclerosis. 2337 82

Polycystic ovary syndrome (PCOS) is a common endocrine disease in women during reproductive age. It was shown that PCOS women are with high risk for dyslipidemia, glucose intolerance, type 2 diabetes and metabolic syndrome. These factors are considered to represent traditional risk factors for the occurrence of cardiovascular disease. Observed increased risk for hypertension in PCOS women seems to be associated with insulin resistance and hyperinsulinemia. Both conditions interfere with the endothelium-dependent vasodilatation mechanisms causing vascular muscle wall hypertrophy. Obesity and insulin resistance are considered key factors for the alteration of blood pressure in PCOS women. Higher cardiovascular risk is implicated in PCOS with aging and its consequent association with both systolic and diastolic blood pressure. The elements of renin-angiotensin-aldosterone system (RAAS) have an impact on endothelial dysfunction as a marker of cardiovascular damage that could be modified is women with PCOS. Androgens and components of RAAS are involved in the process of atherogenesis in PCOS women. Therefore, it is hypothesized that spironolactone treatment could ameliorate endothelial dysfunction in PCOS women. Recently it was shown that telmisartan, angiotensin II receptor antagonist poses insulinsensitizing capacity to activate PPAR gamma and mediate favorable metabolic and reproductive effects in hypertensive PCOS women.
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PMID:Hypertension in Polycystic Ovary Syndrome: Novel Insights. 3114 68