Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The homozygous form of the autosomal dominant disorder, familial hypercholesterolemia, is characterized by the presence in children of profound hypercholesterolemia, cutaneous planar xanthomas, and rapidly progressive coronary vascular disease that usually results in death before age 30 years. Cultured skin fibroblasts from three unrelated subjects with this disorder showed 40- to 60-fold higher activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34), the rate-controlling enzyme in cholesterol biosynthesis, when compared with fibroblasts of seven control subjects. Enhanced enzyme activity resulted from a complete absence of normal feedback suppression by low-density lipoproteins, which led to a marked overproduction of cholesterol by the mutant cells. The demonstration of apparently identical kinetic properties of the reductase activity of control and mutant cells, coupled with the evidence that this enzyme is normally regulated not by allosteric effectors but by alterations in enzyme synthesis and degradation, suggests that the primary genetic abnormality does not involve the structural gene for the enzyme itself, but a hitherto unidentified gene whose product is necessary for mediation of feedback control by lipoproteins. The fibroblasts of two obligate heterozygotes, the parents of one of the homozygotes, showed a pattern of enzyme regulation intermediate between that of controls and homozygotes.
 ...
PMID:Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. 435 66

Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.
 ...
PMID:Effects of pravastatin treatment on vitamin D metabolites. 785 42

Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia.
 ...
PMID:Prevention of stroke and dementia with statins: Effects beyond lipid lowering. 1261 95

Clinical trial evidence strongly favors aggressive risk factor modification in the prevention of coronary artery disease (CAD). The latest landmark trial of therapy using a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is the Heart Protection Study (HPS) of simvastatin versus placebo in a cohort of patients at high risk for CAD. The HPS reported a number of highly significant reductions in the risk for major vascular events with treatment. It also provides new insights into the effects of statin therapy in patient subgroups, such as the elderly, women, and those with noncoronary vascular disease. These data are likely to have an important influence on the future of cardiovascular disease prevention.
 ...
PMID:The Heart Protection Study: expanding the boundaries for high-risk coronary disease prevention. 1286 49

The metabolic syndrome is associated with increased morbility and mortality for cardiovascular disease. This syndrome is determined not only by metabolic alterations such as hyperglycemia, and hyperlipidemia but also by a chronic proinflammatory state. Another culprit in the formation and progression of vascular disease is the so-called endothelial dysfunction which is linked to insulin resistance itself. The common denominator of the metabolic syndrome is insulin resistance. The most convincing evidence for the existence of a syndrome comes from the cluster analysis which outlines four main factors: the "metabolic factor", the "pressor factor", the "lipid factor", and the "obesity factor". It is clear that the presence of the metabolic syndrome appears to identify a substantial additional cardiovascular risk above the individual risk factors. The studies available in the literature have pointed out the beneficial effects, in terms of cardiovascular mortality, of the treatment with inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins): this risk reduction has been observed despite the fact that high triglyceride and low HDL cholesterol levels, but not hypercholesterolemia, are the main features of the dyslipidemia observed in patients with this syndrome. Yet, despite a normal LDL cholesterol level, patients with this syndrome are at high risk for future cardiovascular events: for this reason treatment with statins is mandatory.
 ...
PMID:[Diabetes and multimetabolic syndrome]. 1498 43

The ability of the endothelium to produce nitric oxide is essential to maintenance of vascular homeostasis; disturbance of this ability is a major contributor to the pathogenesis of vascular disease. In vivo studies have demonstrated that expression of endothelial nitric oxide synthase (eNOS) is vital to endothelial function and have led to the understanding that eNOS expression is subject to modest but significant degrees of regulation. Subsequently, numerous physiological and pathophysiological stimuli have been identified that modulate eNOS expression via mechanisms that alter steady-state eNOS mRNA levels. These mechanisms involve changes in the rate of eNOS gene transcription (transcriptional regulation) and alteration of eNOS mRNA processing and stability (posttranscriptional regulation). In cultured endothelial cells, shear stress, transforming growth factor-beta1, lysophosphatidylcholine, cell growth, oxidized linoleic acid, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and hydrogen peroxide have been shown to increase eNOS expression. In contrast, tumor necrosis factor-alpha, hypoxia, lipopolysaccaride, thrombin, and oxidized LDL can decrease eNOS mRNA levels. For many of these stimuli, both transcriptional and posttranscriptional mechanisms contribute to regulation of eNOS expression. Recent studies have begun to further define signaling pathways responsible for changes in eNOS expression and have characterized cis- and trans-acting regulatory elements. In addition, a role has been identified for epigenetic control of eNOS mRNA levels. This review will discuss transcriptional and posttranscriptional regulation of eNOS with emphasis on the molecular mechanisms that have been identified for these processes.
 ...
PMID:Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression. 1673 3

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.
 ...
PMID:Statin withdrawal: clinical implications and molecular mechanisms. 1694 51

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are important for preventing adverse cardiovascular events not only in patients with a high risk of vascular disease but also in those with a low risk, by reducing the levels of low-density lipoprotein cholesterol. Statin is associated with deteriorating glucose homeostasis and an increased risk of diabetes mellitus. Moreover, these off-target effects are dose-dependent; it has also been suggested that renal insult can be caused dose-dependently by statin treatment, in contrast to previous studies showing a renoprotective effect. The 2013 American College of Cardiology/American Heart Association guidelines recommend the use of high-intensity statin therapy, and extend its use to more people at risk of vascular diseases. However, a European committee has expressed concerns about the potential side effects of using statins in a large fraction of the population for extended periods. This is true of Asian people, for whom the disease burden from cardiovascular disorders is not as great as among Western ethnic groups. There are still many unanswered questions on how to balance the cardiovascular benefits with the potential renometabolic risks of statins. Therefore, genetic or pharmacogenetic approaches are needed to define who is more vulnerable to developing diabetes mellitus or acute kidney injury. In particular, more information is required regarding the metabolism of statins, and their off-target or unknown actions and overall impact. These different renometabolic effects of statins should help in formulating optimal therapeutic strategies for patients for reducing overall morbidity and mortality and not just those associated with cardiovascular diseases.
...
PMID:How to balance cardiorenometabolic benefits and risks of statins. 2497 95