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 receptor-gamma (PPARgamma), an orphan nuclear receptor, mediates adipocyte differentiation and is the cellular target for the thiazolidinedione group of insulin-sensitizing antidiabetic agents. We screened this receptor gene in a cohort of subjects with severe insulin resistance and have identified heterozygous missense mutations in several individuals from three families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild type PPARgamma action in a dominant-negative manner. The clinical phenotype of patients includes partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Factors which contribute to the severe insulin resistance in affected individuals include diminished body fat mass, impaired lipid flux in adipose tissue and reduced circulating levels of adiponectin. In a large kindred of five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARGAMMA; and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A). The frameshift PPARgamma mutant exhibits complete loss of function with no dominant-negative activity; the PPP1R3A truncation mutant is mislocalized intracellularly. Individuals harbouring either gene defect alone have normal circulating insulin levels, but a combination of both genetic abnormalities co-segregates with severe insulin resistance.
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PMID:Peroxisome proliferator-activated receptor-gamma and insulin action: insights from human genetics. 1467 97

HIV-associated lipodystrophy syndrome is a syndrome occurring in HIV-infected patients who were treated with highly-active antiretroviral therapy (HAART), especially regimen containing protease inhibitors. The syndrome consists of fat redistribution, with loss of subcutaneous fat and increase in visceral fat, and metabolic disturbances, including glucose intolerance or overt diabetes and dyslipidemia. No standard treatment has been established for this syndrome. Pioglitazone is an oral antidiabetic agent that acts primarily on adipose tissue to reduce insulin resistance. The authors report a 50-year old HIV-infected woman who developed HIV-associated lipodystrophy syndrome after 3 months of HAART. She had significant weight loss with obvious loss of subcutaneous fat, together with development of hypertension, diabetes and dyslipidemia. After treatment with 30 milligrams of pioglitazone daily, her body weight increased within the first month of treatment. Subcutaneous fat loss was restored. Improvement in glycemic and lipid control was also noted. CT scan of the abdomen revealed that fatty infiltration in the liver was markedly decreased. Visceral fat as assessed by CT scan had also decreased. Pioglitazone appeared to have beneficial effects in this patient.
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PMID:Improvement of fat redistribution, insulin resistance and hepatic fatty infiltration in HIV-associated lipodystrophy syndrome by pioglitazone: a case report. 1506

The metabolic syndrome is intended to identify patients who have increased risk of diabetes and/or a cardiac event due to the deleterious effects of weight gain, sedentary lifestyle, and/or an atherogenic diet. The National Cholesterol Education Program's Adult Treatment Panel III definition uses easily measured clinical findings of increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. The authors also note that other definitions of metabolic syndrome focus more on insulin resistance and its key role in this syndrome. This review focuses on how treatment might affect each of the five components. Abdominal obesity can be treated with a variety of lower calorie diets along with regular exercise. Indeed, all of the five components of the metabolic syndrome are improved by even modest amounts of weight loss achieved with diet and exercise. For those with impaired fasting glucose tolerance, there is good evidence that a high fiber, low saturated fat diet with increased daily exercise can reduce the incidence of diabetes by almost 60%. Of note, subjects who exercise the most, gain the most benefit. Metformin has also been shown to be helpful in these subjects. Thiazolidinedione drugs may prove useful, but further studies are needed. Although intensified therapeutic lifestyle change will help the abnormal lipid profile, some patients may require drug therapy. This review also discusses the use of statins, fibrates, and niacin. Likewise, while hypertension in the metabolic syndrome benefits from therapeutic lifestyle change, physicians should also consider angiotensin converting enzyme inhibitor drugs or angiotensin receptor blockers, due to their effects on preventing complications of diabetes, such as progression of diabetic nephropathy and due to their effects on regression of left ventricular hypertrophy. Aspirin should be considered in those with at least a 10% risk of a coronary event over 10 years. Finally, three related conditions, nonalcoholic fatty liver disease, polycystic ovary syndrome and protease inhibitor associated lipodystrophy improve with therapeutic lifestyle change. Although metformin is shown to be useful with polycystic ovary syndrome, the data supporting drug therapy for the other syndromes is less convincing. More robust studies are needed before any firm recommendations can be made.
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PMID:Treatment of metabolic syndrome. 1515 70

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.
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PMID:Phenomics, lipodystrophy, and the metabolic syndrome. 1517 63

Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis. Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.
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PMID:Laminopathies and atherosclerosis. 1520 20

Lipodystrophy and insulin resistance are the core features of human PPARgamma deficiency states. Metabolic complications in PPARgamma deficiency, such as hypertension, have been considered to be secondary to insulin resistance. However, a new mouse model that expresses the analog of a human PPARG mutation displays minimal lipodystrophy and insulin resistance but rather severe hypertension. Furthermore, the mutant protein appears to directly modulate the renin-angiotensin system in adipose tissue, providing evidence of the pleiotropic effects of PPARgamma.
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PMID:Unbuckling lipodystrophy from insulin resistance and hypertension. 1525 91

HIV infection is a global public health issue that is frequently associated with cardiovascular involvement. These HIV-associated cardiovascular manifestations are often clinically occult or attributed incorrectly to other non-cardiac disease processes. A heightened awareness and routine screening for cardiovascular involvement in HIV-infected patients leads to earlier detection and the hope for a reduction in associated morbidity and mortality. Left ventricular dysfunction, an independent predictor of mortality in HIV-infected patients, is the result of many causes in this population and may result in dilated cardiomyopathy and congestive heart failure in about 10% of patients. Other HIV-associated cardiovascular problems include infective endocarditis, cardiovascular malignancy, pulmonary arterial hypertension, vasculitis, pericardial effusion, premature atherosclerosis, and arrhythmias. HIV-associated cardiovascular emergencies include congestive heart failure, pulmonary edema, supraventricular and ventricular arrhythmias, endocarditis, and tamponade. Anti-infective and immunomodulatory therapies may be particularly helpful in this population to reduce associated cardiovascular disease. Highly active antiretroviral therapy may result in lipodystrophy, hyperlipidemia, truncal adiposity, and insulin resistance that can be improved by physical activity and training programs. Cardiovascular complications of therapeutic drugs in HIV-infected patients include torsade de pointes, congestive heart failure, dyslipidemia, accelerated atherosclerosis, and myocardial infarction. In summary, cardiovascular complications are important contributors to morbidity and mortality in HIV-infected patients that can be detected early in many cases and treated effectively.
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PMID:HIV-related cardiovascular disease and drug interactions. 1544 73

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor with a key role in adipocyte differentiation. Since 1997, studies of rare mutations and common polymorphisms of the PPARgamma gene have enabled us to expand our knowledge of the role of this transcription factor in humans. Rare monogenic mutations in PPARgamma have a limited impact on the health of the population due to their low frequency but are associated with severe phenotypes such as severe insulin resistance, partial lipodystrophy, type 2 diabetes and hypertension. Conversely, common polymorphisms of PPARgamma with a relatively high frequency can have a significant impact on the general population. Although they may modulate the risk of developing type 2 diabetes, obesity and cardiovascular diseases, the data remains controversial. This review details and discusses results obtained for PPARgamma variants, whose effects sometimes appear discordant.
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PMID:Impact of genetic variation of PPARgamma in humans. 1546 24

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

Reported here is a case of a patient with pulmonary arterial hypertension related to HIV (PAHRH) in which lipodystrophy necessitated interruption of highly active antiretroviral therapy (HAART) and long-term survival was the outcome. Although previous studies have suggested antiretroviral therapy may benefit patients with this rare complication of HIV infection, no worsening of PAHRH was observed when HAART was interrupted. Clinical and echocardiographic parameters remained stable during 7 months of follow up. In cases in which HAART is associated with relevant toxicity, interruption of HAART in patients with PAHRH can be considered, but should be used only if no alternatives are available. Close follow-up is warranted.
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PMID:Long-term survival and interruption of HAART in HIV-related pulmonary hypertension. 1571 84


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