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)

Mild hyperhomocysteinemia is considered an important risk factor for vascular disease. A common polymorphism (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased enzyme activity and consequent higher circulating levels of homocysteine. We hypothesized that the serum levels of homocysteine and/or the MTHFR polymorphism could influence the risk for coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolemia (FH), who are genetically prone to atherosclerosis. We determined the MTHFR genotype and fasting total serum homocysteine level in 249 adult patients (103 males and 146 females) with heterozygous FH. MTHFR polymorphism was a major determinant of serum homocysteine in adult FH of both sexes. The logistic regression analysis showed that in FH patients a high level of homocysteine (> 12 micromol/l, corresponding to the upper quartile of serum distribution) was the most significant predictor of CAD (n=99) in all the groups considered (all CAD, previous myocardial infarction, myocardial infarction plus angiographically confirmed CAD). The adjusted odds ratio (OR (95% CI)) for the homocysteine-associated risk of CAD (upper quartile versus lower quartiles) was 3.27 (1.60-6.62) in males and females considered together, 5.67 (1.50-21.3) in males and 2.78 (1.17-6.62) in females. LDL cholesterol (upper quartile versus lower quartiles) and hypertension were the other variables independently associated with CAD. In both sexes MTHFR polymorphism was not an independent predictor of CAD. Plasma concentration of serum homocysteine, but not MTHFR genotype, is associated with an increased risk of CAD in male and female patients with heterozygous FH.
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PMID:Serum homocysteine, methylenetetrahydrofolate reductase gene polymorphism and cardiovascular disease in heterozygous familial hypercholesterolemia. 1577 50

The endothelial lectinlike, oxidatively (ox-) modified LDL receptor LOX-1 is a critical player in the pathogenesis of atherosclerosis and myocardial ischemia. Ox-LDL binding of LOX-1 results in the expression of various adhesion molecules, which attract monocytes to endothelial cells, an initial step in atherogenesis. We wished to examine the role of the ox-LDL/LOX-1 signaling pathway in fibroblasts, which naturally express low levels of LOX-1. Rat cardiac fibroblasts were transfected with either cytomegalovirus (CMV)-LOX-1wt (amino acids [aa] 1 to 273) or CMV-LOX-1(1-261) (an ox-LDL-binding negative mutant, aa 1 to 261) plasmid. Western blots showed that LOX-1 protein expression was increased significantly in cells transfected with CMV-LOX-1wt or CMV-LOX-1(1-261) plasmid (P<0.01 vs control). Fibroblasts transfected with CMV-LOX-1wt showed ox-LDL binding, whereas fibroblasts without transfection and those transfected with CMV-LOX-1(1-261) did not bind ox-LDL. Compared with untransfected cells, ox-LDL treatment (50 microg/mL, 24 hours) markedly induced the expression of the leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM)-1 as well as matrix metalloproteinase (MMP)-1 in cells transfected with CMV-LOX-1wt (P<0.05) but not in cells transfected with CMV-LOX-1(1-261). Concurrently, ox-LDL treatment enhanced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) (P<0.05 vs control) in CMV-LOX-1wt-transfected cells. These data suggest that in cardiac fibroblasts, ox-LDL binds to LOX-1 and activates p38 MAPK, followed by the expression of ICAM-1, VCAM-1, and MMP-1. Thus, fibroblasts transform into an endothelial phenotype on transfection with CMV-LOX-1wt and subsequent exposure to ox-LDL. This study provides a useful model system (plasmid-transfected fibroblasts) to study the molecular biology of LOX-1.
Hypertension 2005 Sep
PMID:Adhesion molecule expression in fibroblasts: alteration in fibroblast biology after transfection with LOX-1 plasmids. 1611 44

Familial hypercholesterolaemia is a genetic disorder characterised by high low-density lipoprotein (LDL) cholesterol concentrations, which frequently gives rise to premature coronary artery disease (CAD). The clinical expression of familial hypercholesterolaemia is highly variable even in patients carrying the same LDL receptor gene mutation. This variability may be due to environmental and other genetic factors. Apolipoprotein E (Apo-E) has been extensively studied for its effects on the phenotype of familial hypercholesterolaemia. In this study we examined the influence of Apo-E genotype on lipid parameters and the incidence of CAD in 93 Greek patients with familial hypercholesterolaemia. Apo-E E2, E3 and E4 allele frequencies were 0.06, 0.86 and 0.09 respectively. The levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins A and B and lipoprotein alpha did not differ significantly among carriers and non-carriers of the E4 allele. The prevalence of CAD and hypertension did not differ either. Our results suggest that the E4 allele is not associated with lipid levels or with the prevalence of CAD among familial hypercholesterolaemia patients of the Greek population.
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PMID:Apolipoprotein E polymorphism is not associated with lipid levels and coronary artery disease in Greek patients with familial hypercholesterolaemia. 1636

Accumulating evidence supports an autoimmune mechanism as one of the prime pathogenic processes involved in the development of atherosclerosis. So far, three proteins, including heat shock proteins (HSPs), oxidized low-density lipoprotein (oxLDL), and beta2 glycoprotein1 (beta2GP1) have been recognized as autoantigens. It has been demonstrated that risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, infections, and oxidative stress, evoke increased expression of HSPs in cells of atherosclerotic lesions. Autoantibody levels against HSPs are significantly increased in patients with atherosclerosis and T lymphocytes specifically responding to these autoantigens have been demonstrated within atherosclerotic plaques. Subcutaneous immunization of animals with HSP65 induced atheroma formation in the arterial wall. Furthermore, circulating immunoglobulin (Ig) G and IgM oxidized low-density lipoprotein (oxLDL) antibodies are present in the plasma of animals and humans and form immune complexes with oxLDL in atherosclerotic lesions. These antibodies closely correlate with the progression and regression of atherosclerosis in murine models. Interestingly, recent reports demonstrated that pneumococcal vaccination to LDL receptor-deficient mice results in elevation of anti-oxLDL IgM Ab EO6, which is inversely correlated with the development of atherosclerosis. Finally, it has been observed that autoantigen beta2GP1 localizes in the atheroma and that autoantibodies to beta2GP1 are correlated with the incidence of atherosclerosis in patients. Hence, these autoimmune reactions to HSPs, oxLDL and beta2GP1 can contribute to the initiation and progression of atherosclerosis.
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PMID:Autoimmune mechanisms of atherosclerosis. 1659 21

Increased angiotensin II (Ang II) sensitivity predisposes to hypertension and plaque instability. Raised low-density lipoprotein cholesterol (LDL-c) may increase Ang II sensitivity, but evidence in humans for this effect of LDL-c is limited. In 28, healthy, nonsmoking subjects, aged 30+/-8 years, with familial hypercholesterolemia, we determined the difference in infusion rate of Ang II and norepinephrine required to increase systolic blood pressure by 20 mm Hg (Pd-20) after 4 weeks of placebo and fluvastatin 80 mg daily in a randomized, double-blind, placebo-controlled, crossover study. Before infusions were started, fasting blood samples were taken to measure lipids. After 4 weeks of placebo, the mean LDL-c concentration was 6.3+/-1.4 mmol/L. The average decrease of LDL-c was 1.7+/-0.7 mmol/L after 4 weeks of fluvastatin (P<0.001). The mean Pd-20 for Ang II increased by 1.28 ng/kg per minute (95% CI, 2.05 to 0.50; P=0.002) on fluvastatin, corresponding with a 26% decrease in Ang II sensitivity. Ang II sensitivity, however, remained increased compared with normocholesterolemic controls. The Pd-20 values for norepinephrine were unaffected by fluvastatin. The present study in healthy, young subjects with isolated hypercholesterolemia shows an increased sensitivity to Ang II that partly can be restored by LDL-c-lowering therapy. These findings indicate that LDL-c levels directly influence Ang II sensitivity.
Hypertension 2006 Jun
PMID:Effect of low-density lipoprotein cholesterol on angiotensin II sensitivity: a randomized trial with fluvastatin. 1661 34

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are the most successful cardiovascular drugs of all time. By interrupting cholesterol synthesis in the liver, they activate hepatocyte low-density lipoprotein (LDL) receptors and produce consistent and predictable reductions in circulating LDL cholesterol with resulting reproducible improvements in cardiovascular risk by retarding or even regressing the march of atherosclerosis in all major arterial trees (coronary, cerebral and peripheral). Clinical trials have demonstrated their capacity not only to extend life, but also to improve its quality by retarding the progression of diabetes mellitus and chronic renal disease and by enhancing central and peripheral blood flow. They are amongst the most extensively investigated pharmaceutical agents in current clinical use. In cardiovascular end-point trials they have proven ability to help prevent that first and all important myocardial infarction and to reduce the likelihood of a recurrence in those who do succumb. They are equally effective in men and women of all ages and at all levels of cardiovascular risk, whether caused by hypercholesterolaemia, hypertension, cigarette smoking, diabetes mellitus or the metabolic syndrome. In addition, they improve the outlook of patients with familial hypercholesterolaemia whose LDL receptor function is deficient or defective; and all of this comes at minimal risk to the recipient. Their most important potential side effect is myopathy, which on very rare occasions may lead to rhabdomyolysis. Clinical experience shows that myopathic symptoms with creatine kinase levels raised to more than 10 times the upper limit of normal is seen in <0.01% of recipients and progression to fatal rhabdomyolysis because of renal failure has been recorded in only 0.15 cases per million prescriptions. Liver function abnormalities are also, rarely, seen. Again, the frequency of raised aspartate or alanine aminotransferase to more than three times the normal limit is encountered in no more than 1-2% of all treated patients and is completely reversible upon withdrawal of treatment. Progression to hepatitis or liver failure does not occur. This constellation of benefits with little side effect penalty has resulted in the comparison of statins with antibiotics in the global battle against cardiovascular disease.
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PMID:Who should receive a statin these days? Lessons from recent clinical trials. 1696 68

Gene transfer for the therapeutic modulation of cardiovascular diseases is an expanding area of gene therapy. During the last decade several approaches have been designed for the treatment of hyperlipidemias, post-angioplasty restenosis, hypertension, and heart failure, and for protection of vascular by-pass grafts and promotion of therapeutic angiogenesis. Adenoviruses (Ads) and adeno-associated viruses (AAVs) are currently the most efficient vectors for delivering therapeutic genes into the cardiovascular system. Gene transfer using local gene delivery techniques have been shown to be superior to less-targeted intra-arterial or intra-venous applications. To date, no gene therapy drugs have been approved for clinical use in cardiovascular applications. In preclinical studies of therapeutic angiogenesis, various growth factors such as vascular endothelial growth factors (VEGFs) and fibroblast growth factors (FGFs), have shown positive results. Gene therapy also appears to have potential clinical applications in improving the patency of vascular grafts and in treating heart failure. Post-angioplasty restenosis, hypertension, and hyperlipidemias (excluding homozygotic familial hypercholesterolemia) can usually be managed satisfactorily by conventional approaches, and are therefore less favored areas for gene therapy. The development of technologies that can ensure long-term, targeted, and regulated gene transfer, and a careful selection of target patient populations, will be very important for the progress of cardiovascular gene therapy in clinical applications.
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PMID:Current status of cardiovascular gene therapy. 1750 81

Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically and will develop lesions comparable to those in humans. The mouse is the most useful, economic, and valid model for studying atherosclerosis and exploring effective therapeutic approaches. Among the most widely used mouse models for atherosclerosis are apolipoprotein E-deficient (ApoE-/-) and LDL receptor-deficient (LDLr-/-) mice. An up-and-coming model is the ApoE*3Leiden (E3L) transgenic mouse. Here, we review studies that have explored how and to what extent these mice respond to compounds directed at treatment of the risk factors hypercholesterolemia, hypertriglyceridemia, hypertension, and inflammation. An important outcome of this survey is that the different models used may differ markedly from one another in their response to a specific experimental manipulation. The choice of a model is therefore of critical importance and should take into account the risk factor to be studied and the working spectrum of the compounds tested.
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PMID:Mouse models for atherosclerosis and pharmaceutical modifiers. 1754 Oct 27

The serum lipoprotein(a) [Lp(a)] concentration is under genetic control, and most humans have values lower than 30 mg/dL. Subjects with markedly elevated serum Lp(a) concentrations, that is, > or =100 mg/dL, are rarely encountered, and these subjects have not yet been fully characterized from the clinical point of view. In the present investigation, we studied a total of 223 subjects, comprising 123 males and 100 females, with serum Lp(a) values of more than 100 mg/dL. Many of these subjects had a variety of underlying diseases, including metabolic disorders, renal diseases, and hypertension. We focused our attention on the patients with metabolic disorders, namely, familial hypercholesterolemia (FH), primary non-FH hypercholesterolemia (HC), and type 2 diabetes mellitus (DM), and conducted a comparative study of the patients of these 3 disease groups with the corresponding disease controls with serum Lp(a) levels of less than 30 mg/dL, a presumed high normal value. The frequency of markedly elevated serum Lp(a) levels in the general population has not been reported previously. We determined the frequencies in a consecutive series of patients at our Diabetes and Lipid Outpatient Clinic; the results revealed that the frequencies were 6.4% (8/125), 2.6% (6/232), and 0.9% (3/352) in patients with FH, HC, and type 2 DM, respectively. In an attempt to further demonstrate the impact of markedly elevated serum Lp(a) concentrations on the risk of coronary heart disease (CHD), we compared the prevalence of CHD among the study subjects with that among the corresponding disease controls. The results revealed a significantly higher CHD prevalence in the study subjects of all the 3 groups as compared with that in the corresponding disease controls: the odds ratios of a markedly elevated serum Lp(a) level were 5.429 (95% confidence interval [CI], 1.353-21.782), 8.243 (95% CI, 2.793-24.327), and 5.981 (95% CI, 2.530-14.139) for FH, HC, and type 2 DM, respectively. In the present study, we examined some characteristics of this rare population of subjects with markedly elevated serum Lp(a) levels and demonstrated a very high prevalence of CHD among these patients with FH, HC, and type 2 DM, strongly suggesting the significance of Lp(a) as a risk factor for CHD.
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PMID:Impact of markedly elevated serum lipoprotein(a) levels (> or = 100 mg/dL) on the risk of coronary heart disease. 1769 60

We investigated the ability of S-nitroso-N-acetylcyseine (SNAC) to prevent structural and functional myocardial alterations in hypercholesterolemic mice. C57BL6 wild-type (WT) and LDL-R-/- male mice (S) were fed a standard diet for 15 days. LDL-R-/- mice (S) showed an 11% increase in blood pressure, 62% decrease in left atrial contractility, and lower CD40L and eNOS expression relative to WT. LDL-R-/- mice fed an atherogenic diet for 15 days (Chol) showed significant increased left ventricular mass compared to S, which was characterized by: (1) 1.25-fold increase in the LV weight/body weight ratio and cardiomyocyte diameter; (2) enhanced expression of the NOS isoforms, CD40L, and collagen amount; and (3) no alteration in the atrial contractile performance. Administration of SNAC to Chol mice (Chol + SNAC) (0.51 micromol/kg/day for 15 day, IP) prevented increased left ventricular mass, collagen deposit, NOS isoforms, and CD40L overexpression, but it had no effect on the increased blood pressure or atrial basal hypocontractility. Deletion of the LDL receptor gene in mice resulted in hypertension and a marked left atrial contractile deficit, which may be related to eNOS underexpression. Our data show that SNAC treatment has an antiinflammatory action that might contribute to prevention of structural and functional myocardial alterations in atherosclerotic mice independently of changes in blood pressure.
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PMID:S-nitroso-N-acetylcysteine (SNAC) prevents myocardial alterations in hypercholesterolemic LDL receptor knockout mice by antiinflammatory action. 1820 72


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