Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.
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PMID:Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators. 1263 6

Transgenic mice overexpressing growth hormone (GH) have been extensively used to study the chronic effects of elevated serum levels of GH. GH is known to have many acute effects in the liver, but little is known about the chronic effects of GH overexpression on hepatic gene expression. Therefore, we used DNA microarray to compare gene expression in livers from bovine GH (bGH)-transgenic mice and littermates. Hepatic expression of peroxisome proliferator-activated receptor-alpha (PPARalpha) and genes involved in fatty acid activation, peroxisomal and mitochondrial beta-oxidation, and production of ketone bodies was decreased. In line with this expression profile, bGH-transgenic mice had a reduced ability to form ketone bodies in both the fed and fasted states. Although the bGH mice were hyperinsulinemic, the expression of sterol regulatory element-binding protein (SREBP)-1 and most lipogenic enzymes regulated by SREBP-1 was reduced, indicating that these mice are different from other insulin-resistant models with respect to expression of SREBP-1 and its downstream genes. This study also provides several candidate genes for the well-known association between elevated GH levels and cardiovascular disease, e.g., decreased expression of scavenger receptor class B type I, hepatic lipase, and serum paraoxonase and increased expression of serum amyloid A-3 protein. We conclude that bGH-transgenic mice display marked changes in hepatic genes coding for metabolic enzymes and suggest that GH directly or indirectly regulates many of these hepatic genes via decreased expression of PPARalpha and SREBP-1.
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PMID:Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes. 1273 63

Increasing attention has focused on the role of inflammation in various chronic diseases, including atherosclerosis. Recent compelling data have begun to unite work from various arenas, such as epidemiology and vascular biology, and even clinical trials to provide evidence for inflammation as a mechanism underlying cardiovascular disease. Inflammation has been implicated in the pathogenesis, progression, and complications of both atherosclerosis and diabetes mellitus-2 complex disorders often found intertwined in patients. Although this story continues to evolve, peroxisome proliferator-activated receptors (PPARs) have been implicated as a molecular pathway involved in both these disease processes. In vitro data, animal work, and some human studies suggest that synthetic PPAR agonists in clinical use, such as thiazolidinediones, may not only regulate metabolic processes but may also limit inflammatory responses, including some involved in atherosclerosis.
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PMID:The potential role of peroxisome proliferator-activated receptors on inflammation in type 2 diabetes mellitus and atherosclerosis. 1295 25

K-111, formerly BM 17.0744, (2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid) is a new insulin-sensitizer with peroxisome proliferator-activated receptor (PPAR) alpha activity but without PPAR gamma activity. We determined the efficacy of K-111 in non-human primates in increasing insulin-stimulated glucose uptake and improving metabolic syndrome, assessing the general health-related effects. Six adult male obese normoglycemic prediabetic and insulin-resistant rhesus monkeys were studied on vehicle and following K-111 treatment (four-week chronic dosing each of 3 doses: 1, 3, and 10 mg/kg/d) with assessment of changes in substrate, hormone, and blood pressure measurements and alterations in insulin sensitivity using the euglycemic, hyperinsulinemic clamp technique. K-111 led to significantly decreased body weight and improved hyperinsulinemia, insulin sensitivity, hypertriglyceridemia, and HDL-cholesterol levels without adipogenesis or significant effects on fasting glucose, 24-hour urine glucose excretion, systolic or diastolic blood pressure, plasma fibrinogen, total cholesterol, or chemistry and hematology profile. These benefits are similar to the health-improving effects of calorie restriction, providing preliminary evidence that K-111 has excellent potential as a calorie-restriction mimetic agent. These results indicate the necessity of future study of K-111 for metabolic syndrome in humans, and suggest potential in reducing the risks of diabetes and cardiovascular disease.
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PMID:The effects of K-111, a new insulin-sensitizer, on metabolic syndrome in obese prediabetic rhesus monkeys. 1460 98

The vascular endothelium is an active, dynamic tissue that controls many important functions, including regulation of vascular tone and maintenance of blood circulation, fluidity, coagulation, and inflammatory responses. Cardiovascular risk factors affect many of the normal functions of the endothelium. In particular, oxidized low-density lipoprotein cholesterol initiates a series of events that begin with cell activation, endothelial dysfunction, local inflammation, and a procoagulant vascular surface. These conspire to result in plaque formation and ultimately plaque rupture and cardiovascular events. Endothelial dysfunction may be evaluated by means of invasive techniques, such as coronary artery reactivity to acetylcholine, or noninvasive techniques, such as brachial artery ultrasonography. Loss of endothelium-dependent vasodilation is a characteristic feature throughout the development of atherosclerosis, and it is independently related to future adverse cardiovascular risk. Therefore, measurement of endothelial function can possibly be used to determine risk, to triage management, and to improve outcomes. At the same time, inflammation is a crucial factor in the atherosclerotic disease process. To identify and monitor the ongoing inflammatory process, markers of inflammation such as C-reactive protein (CRP) have been studied. Scientific evidence shows that elevated plasma CRP values add to the predictive ability of other established risk factors; moreover, elevated values appear to augment the Framingham Coronary Risk Score in identifying individuals who should be considered for cardioprotective treatment programs. Interestingly, thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-gamma agonists that are effective in the treatment of type 2 diabetes mellitus, not only increase insulin sensitivity but can benefit endothelial function because they exhibit anti-inflammatory effects. For many individuals, including those with the metabolic syndrome and/or type 2 diabetes, endothelial dysfunction and elevated plasma CRP levels indicate increased risk of cardiovascular disease. Notably, the TZDs have been shown to reduce CRP levels and may improve endothelial function.
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PMID:Endothelial function, inflammation, and prognosis in cardiovascular disease. 1467 74

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.
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PMID:Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. 1500 34

Patients with type 2 diabetes are at high risk of cardiovascular disease. In addition to treating hyperglycemia, the thiazolidinedione (TZD) class of antidiabetic agents may also benefit the cardiovascular complications associated with the disease. The two available TZDs, pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists that influence gene expression of key proteins involved in regulating glucose and lipid metabolism. Tumor necrosis factor-alpha (TNF-alpha) and adiponectin are believed to be important in the development of insulin resistance and atherosclerosis. Understanding the role of these cytokines in the inflammatory processes that trigger plaque development might lead to identification of other potential mechanisms that could be exploited to enhance future treatments for patients with diabetes and atherosclerosis.
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PMID:What are the effects of peroxisome proliferator-activated receptor agonists on adiponectin, tumor necrosis factor-alpha, and other cytokines in insulin resistance? 1547 Sep 6

Atherosclerosis is an inflammatory process triggered by the presence of lipids in the vascular wall and encompasses a complex interaction between inflammatory cells, vascular elements and lipoproteins through the expression of several adhesion molecules and cytokines. Activation of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation in vitro as well as in animal and human studies. The tissue distribution of PPAR-alpha is extensive and it is abundantly present in the vascular wall where it may mediate many of anti-inflammatory and antiatherogenic effects. Major clinical trials, such as the Veterans Affairs High-Density Lipoprotein Intervention Trial, the Helsinki Heart Study and the Diabetes Atherosclerosis Intervention Study, have demonstrated the beneficial effects of synthetic agonists of PPAR-alpha, specifically fibric acid derivatives, on cardiovascular disease outcome. Although fibric acid trials have reported cardiovascular risk reduction in patients with dyslipidemia, the favorable alterations in plasma lipids can only partially explain the reduction in cardiovascular events in these studies. One common link among these trials was a cohort with a high prevalence of insulin resistance or diabetes, conditions associated with heightened systemic inflammation and increased risk for development and progression of atherosclerosis. In this paper, we will review the many antiatherogenic effects of PPAR-alpha ligands and evidence from fibric acid trials that individuals with insulin resistance or diabetes benefit the most from these drugs, consistent with their anti-inflammatory and antithrombotic properties.
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PMID:Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. 1552 94

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

The treatment of dyslipidemia is beyond doubt one of the cornerstones of cardiovascular prevention. If we want to touch and comment on at least the principal news in this broad field, we must simplify and pay attention to only a few selected areas. The focus of this article is on hypercholesterolemia and the treatment options for elevated low-density lipoprotein (LDL)-cholesterol; it also addresses the questions of low high-density lipoprotein (HDL)-cholesterol levels and the treatment of dyslipidemia of the metabolic syndrome. In particular, statins have had accumulation of new evidence resulting in novel indications and new target groups. Modern, even more potent drugs lowering total and LDL-cholesterol levels are available (new statins, e.g., rosuvastatin, pitavastatin, cholesterol absorption inhibitor ezetimibe) More and more attention of the medical public is being paid to dyslipidemia of the metabolic syndrome (so-called lipid triad), which seems to be the greatest rival of LDL-cholesterol among lipid risk factors for cardiovascular disease. In the treatment of this dyslipidemia especially the nuclear peroxisome proliferator-activated receptor (PPAR) agonists play an important role. In particular fibrates but also glithasones are noteworthy in this respect. There are fewer data for fibrates than for statins, but nevertheless evidence documenting benefit of this therapy is growing. A statin and fibrate combination is a promising future approach not only to the treatment of metabolic syndrome. Moreover, niacin, particularly in combination with a statin, might experience a renaissance. HDL-cholesterol level modification attracts more and more discussions; on the horizon there are new therapies of low HDL, for example, cholesterol-ester transfer protein inhibitors, which have been shown to have a potency for increasing HDL by more than 50%.
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PMID:New strategies in the treatment of dyslipidemia: do we know how? 1563 Jun 30


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