Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Angiogenesis is important in the growth and progression of solid tumours. The main pro-angiogenic factor, namely vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells. The soluble isoform of VEGF is a dimeric glycoprotein of 36-46 kDa, induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine-kinase receptors: VEGF-1 (flt-1) and VEGF-2 (KDR/flk1). An increase in VEGF expression in tumour tissue or some blood compartments (i.e. serum or plasma) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis. Bevacizumab, a recombinant humanised monoclonal antibody developed against VEGF, binds to soluble VEGF, preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation. Pre-clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression. Bevacizumab is the first anti-angiogenetic treatment approved by the American Food and Drug Administration in the first-line treatment of metastatic colorectal cancer. It has shown preliminary evidence of efficacy for breast, non-small-cell lung, pancreatic, prostate, head and neck and renal cancer as well as haematological malignancies. Common toxicities associated with bevacizumab include hypertension, proteinuria, bleeding episodes and thrombotic events. This review summarises the critical role of VEGF and discusses the data available on bevacizumab, from the humanisation of its parent murine monoclonal antibody (mAb) A.4.6.1 to its use in cancer clinical trials.
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PMID:Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. 1684 97

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.
Hypertension 2007 May
PMID:CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt. 1738 51

Interleukin (IL)-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). Here, we investigated the role of these IL-6R components in hypertension and vascular hypertrophy in mice. Angiotensin (Ang) II (1.1 mg/kg/day) caused hypertension and cardiac/aortic hypertrophy in wild-type, but not IL-6(-/-), mice throughout 7 days. A recombinant dimeric soluble gp130 (sgp130Fc; 50 to 100 microg, i.p.) blocked Ang II hypertension but not hypertrophy in wild-type mice. Cognate IL-6R was detected in aortic smooth muscle, but its levels and those of plasma sIL-6R were approximately 50% decreased in IL-6(-/-) mice. Ang II infusion activated signal transducer and activator of transcription-3 in heart of WT and decreased Ang II receptor 1 (ATR1) expression in aorta. Both responses were unaffected by sgp130Fc and absent in IL-6(-/-) mice. In summary, we show that IL-6 trans-signaling is required for Ang II-dependent hypertension, but that hypertrophy, down-regulation of AT1R, and cardiac signal transducer and activator of transcription-3 activation are mediated via cognate IL-6R. These data show that IL-6 responses in a single disease context are governed by both modes of IL-6 signaling, with each pathway eliciting different outcomes. Inhibition of IL-6 signaling is suggested as a potential therapy for hypertension and cardiac hypertrophy.
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PMID:Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo. 1759 76

Peripheral artery disease (PAD) is mostly related to atherosclerosis. Autoimmunity and, in particular, antibodies to cardiolipin (aCL) and phospholipid cofactors such as beta2-glycoprotein I (beta2-gpI) might influence the development of atheroma. Beta2-glycoprotein I (beta2-gpI) has been found in atheroma. It has previously been shown that immunoglobulin A (IgA) anti-beta2-gpI antibodies are associated with a risk of cerebral ischemia and myocardial infarction. This case control study aimed to determine whether elevated levels of aCL/anti-beta2-gpI antibodies are associated with a risk of symptomatic PAD (sPAD). Cases comprised a nonselected population of patients with sPAD (intermittent claudication or critical ischemia). Patient recruitment was based on arteriography changes. Controls were selected from patients admitted to orthopedic wards as a result of fractures or muscle-ligamentous disorders. Age, sex, race, hypertension, smoking, diabetes mellitus, and hypercholesterolemia were evaluated as risk factors in both groups. IgG/IgM/IgA aCL and anti-beta2-gpI were detected by enzyme-linked immunoabsorbant assays (ELISA). To estimate the grade of association of antibodies with sPAD, odds ratios (OR) were calculated. Logistic regression was utilized for adjustment of confounding factors. Seventy-seven cases and 93 controls were studied. The mean age was 61.5 years for cases and 47.5 years for controls (p <0.001). Among the risk factors evaluated, the presence of hypertension showed the strongest association with sPAD (OR 12.1; 95%CI 5.8-30). The presence of IgA anti-beta2-gpI was independently associated with sPAD (OR 5.4; 95%CI 1.8-15.8; p = 0.01). IgA aCL was strongly associated with the outcome (nonadjusted OR 11.5 after Agresti correction). IgA aCL and IgA anti-beta2-gpI antibodies were not associated with any known risk factors for sPAD or with arteriography changes. The occurrence of these autoantibodies might represent one of the links between autoimmunity and atherosclerosis in patients with sPAD.
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PMID:Autoantibodies to the atheroma component beta2-glycoprotein I and risk of symptomatic peripheral artery disease. 1762 83

Platelet membrane glycoprotein receptors mediate key reactions in arterial thrombosis. The relationship between glycoprotein Ia polymorphisms and the risk of ischemic stroke, however, remains controversial. A matched case-control study was conducted to evaluate this question in young patients. Seventy patients with ischemic stroke of undetermined etiology, with ages ranging from 15 to 50 years, and 70 healthy control individuals, matched by age, gender and ethnicity, were tested for the 807C/T genotypes. Patients were excluded if they had systemic diseases known to predispose to thrombosis or any defined etiology of ischemic stroke. The frequencies of the 807T glycoprotein Ia variant and of conventional risk factors for arterial thrombosis (hypertension, smoking, diabetes mellitus, use of oral contraceptives, levels of serum cholesterol and body mass index) were compared in stroke patients and control individuals. The 807T allele was found in 61% of patients and 53% of control individuals (matched-pair odds ratio, 1.38; 95% confidence interval, 0.69-2.74; P = 0.42). Arterial hypertension and smoking were more frequent in patients than control individuals (matched-pair odds ratio, 2.83; 95% confidence interval, 1.05-8.02; P = 0.04; and odds ratio, 3.20; 95% confidence interval, 1.10-9.97, P = 0.03, respectively). In conclusion, our results do not support an independent association between the 807C/T polymorphism and stroke of undetermined etiology. The interplay of this polymorphism with arterial hypertension in the causation of ischemic stroke requires further evaluation.
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PMID:807C/T polymorphism in the platelet glycoprotein Ia gene in young patients with ischemic stroke of undetermined etiology. 1789 Sep 45

Anaemia is a frequent complication in cancer patients and may be multifactorial in origin. Treatment with recombinant human erythropoietin (rHuEPO) is an alternative to red blood cell transfusion. The evidence from clinical trials has established that patients with chemotherapy-induced anaemia with a haemoglobin concentration below 10 g/dl benefit from epoetin therapy. The native glycoprotein hormone consists of 165 amino acids with three N-glycosylation and one O-glycosylation sites. Epoetin and darbepoetin bind to the EPO receptor to induce intracellular signalling by the same intracellular molecules as native EPO. There are some differences in the glycosylation pattern which lead to variations in the pharmacokinetics and pharmacodynamics profiles. Pharmacokinetic and therapeutic studies have examined the use of rHuEPO administered intravenously and subcutaneously and there is accumulating evidence that the latter route has several advantages in cancer patients. After subcutaneous administration, the bioavailability of epoetin is about 20-30% and has a plasma half-life of >24 h. Darbepoetin has a longer half-life after subcutaneous administration of 48 h. The general recommendations are based on evidence from trials in which epoetin was administered 150 U/kg thrice weekly. The recommended initial dose for darbepoetin alpha is 2.25 mug/kg per week. The most serious adverse effects are hypertension, bleeding and increased risk of thrombotic complications. Caution is advised when used in patients who are at high risk for thromboembolic events. In the management of anaemic cancer patients, physicians should closely follow the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines.
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PMID:Erythropoietin pharmacology. 1805 26

A lysosomal storage disease (LSD) results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum-associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil-both US Food and Drug Administration-approved hypertension drugs-partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient-derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely alpha-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety.
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PMID:Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis. 1825 60

von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.
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PMID:A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease. 1868 May 27

EMILIN1 is a glycoprotein of elastic tissues that has been recently linked to the pathogenesis of hypertension. The protein is formed by different independently folded structural domains whose role has been partially elucidated. In this paper the solution structure, inferred from NMR-based homology modelling of the C-terminal trimeric globular C1q domain (gC1q) of EMILIN1, is reported. The high molecular weight and the homotrimeric structure of the protein required the combined use of highly deuterated (15)N, (13)C-labelled samples and TROSY experiments. Starting from a homology model, the protein structure was refined using heteronuclear residual dipolar couplings, chemical shift patterns, NOEs and H-exchange data. Analysis of the gC1q domain structure of EMILIN1 shows that each protomer of the trimer adopts a nine-stranded beta sandwich folding topology which is related to the conformation observed for other proteins of the family. Distinguishing features, however, include a missing edge-strand and an unstructured 19-residue loop. Although the current data do not allow this loop to be precisely defined, the available evidence is consistent with a flexible segment that protrudes from each subunit of the globular trimeric assembly and plays a key role in inter-molecular interactions between the EMILIN1 gC1q homotrimer and its integrin receptor alpha4beta1.
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PMID:NMR-based homology model for the solution structure of the C-terminal globular domain of EMILIN1. 1902 65

Cardiotrophin-1 (CT-1), a member of interleukin (IL)-6 family, was originally isolated for its ability to induce a hypertrophic response in neonatal cardiac myocytes. This cytokine mediates a pleiotropic set of growth and differentiation activities through a unique receptor system, consisting of IL-6 receptor (IL-6R) and a common signal transducer, the glycoprotein 130 (gp130). Both in humans and in mice, CT-1 mRNA has been detected in several tissues, such as liver tissue, adipose tissue, and tissues in the respiratory and nervous systems; in each of these tissues it performs different functions. Predominant actions of CT-1 are on the heart, where it is synthesized and where it provides first myocardial protection by promoting cell survival and proliferation, it carries on its haemodynamic effects and endocrine properties, and finally, it predisposes the heart to pathological conditions. The aim of this review is to describe the pathophysiological mechanisms through which CT-1 carries out its activities, especially on the heart, and its potential contribution as a disease marker in clinical cardiology. Recent studies have confirmed its active role in promoting structural changes typical of most common cardiovascular disease, such as hypertension, valve diseases, congestive heart failure, and coronary artery disease. In fact, CT-1 induces myocyte hypertrophy and collagen synthesis, thereby participating in the progression of ventricular remodelling, which results in cardiac muscle failure at the latest stage. CT-1 plasma levels are elevated in patients with hypertension and coronary artery diseases, and they are also correlated with the severity of valve diseases and heart failure. Therefore, CT-1 may represent a diagnostic, staging, and prognostic biomarker of cardiovascular diseases.
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PMID:Novel insights into the role of cardiotrophin-1 in cardiovascular diseases. 1905 13


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