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)

1. Hypertension is associated with structural alterations of resistance arteries, a process known as remodelling (increased media-to-lumen ratio). 2. At the cellular level, vascular remodelling involves changes in vascular smooth muscle cell (VSMC) growth, cell migration, inflammation and fibrosis. These processes are mediated via multiple factors, of which angiotensin (Ang) II appears to be one of the most important in hypertension. 3. Angiotensin II signalling, via AT1 receptors, is upregulated in VSMC from resistance arteries of hypertensive patients and rats. This is associated with hyperactivation of vascular NADPH oxidase, leading to increased generation of reactive oxygen species (ROS), particularly O2- and H2O2. 4. Reactive oxygen species function as important intracellular second messengers to activate many downstream signalling molecules, such as mitogen-activated protein kinase, protein tyrosine phosphatases, protein tyrosine kinases and transcription factors. Activation of these signalling cascades leads to VSMC growth and migration, modulation of endothelial function, expression of pro-inflammatory mediators and modification of extracellular matrix. 5. Furthermore, ROS increase intracellular free Ca2+ concentration ([Ca2+]i), a major determinant of vascular reactivity. 6. All these processes play major roles in vascular injury associated with hypertension. Accordingly, ROS and the signalling pathways that they modulate provide new targets to regress vascular remodelling, reduce peripheral resistance and prevent hypertensive end-organ damage. 7. In the present review, we discuss the role of ROS as second messengers in AngII signalling and focus on the implications of these events in the processes underlying vascular remodelling in hypertension.
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PMID:Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension. 1467 51

Excess production of superoxide anion in response to angiotensin II plays a central role in the transduction of signal molecules and the regulation of vascular tone. We examined the ability of insulin resistance to stimulate superoxide anion production and investigated the identity of the oxidases responsible for its production. Rats were fed diets containing 60% fructose (fructose-fed rats) or 60% starch (control rats) for 8 weeks. In aortic homogenates from fructose-fed rats, the superoxide anion generated in response to NAD(P)H was more than 2-fold higher than that of control rats. Pretreatment of the aorta from fructose-fed rats with inhibitors of NADPH oxidase significantly reduced superoxide anion production. In the isolated aorta, contraction induced by angiotensin II was more potent in fructose-fed rats compared with control rats. Losartan normalized blood pressure, NAD(P)H oxidase activity, endothelial function, and angiotensin II-induced vasoconstriction in fructose-fed rats. To elucidate the molecular mechanisms of the enhanced constrictor response to angiotensin II, expressions of angiotensin II receptor and subunits of NADPH oxidase were examined with the use of angiotensin II type 1a receptor knockout (AT1a KO) mice. Expression of AT1a receptor mRNA was enhanced in fructose-fed mice, whereas expression of either AT1b or AT2 was unaltered. In addition, protein expression of each subunit of NADPH oxidase was increased in fructose-fed mice, whereas the expression was significantly decreased in fructose-fed AT1a KO mice. The novel observation of insulin resistance-induced upregulation of AT1 receptor expression could explain the association of insulin resistance with endothelial dysfunction and hypertension.
Hypertension 2004 Feb
PMID:Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. 1469 97

Clinical and experimental evidence suggests that the pathways by which hypertension and dyslipidemia lead to vascular disease may overlap and that angiotensin II (Ang II) is involved in restructuring of the arterial wall in both atherosclerosis and hypertension. Ang II represents a potent proinflammatory agent promoting recruitment of monocytes into the vascular intima. Ang II also indirectly facilitates transformation of macrophages and smooth muscle cells into foam cells by promoting superoxide radical formation (via NADP/NADPH oxidase stimulation). The oxidative stress produced by Ang II leads to enhanced low-density lipoprotein oxidation and degradation of nitric oxide, an important vascular protective molecule capable of retarding atherosclerosis progression. The importance of the renin-angiotensin system (RAS) in atherogenesis is highlighted by studies in animal models as well as human beings indicating that inhibition of angiotensin-converting enzyme or blockade of type 1 Ang II receptors retards the development of atherosclerotic lesions. In light of a causal and central role of Ang II in atherogenesis, blockade of the RAS represents an important therapeutic consideration in the prevention and treatment of atherosclerotic disease.
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PMID:Renin-angiotensin system as a therapeutic target in managing atherosclerosis. 1470 95

The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1 receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.
Hypertension 2004 Feb
PMID:Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. 1470 52

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
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PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.
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PMID:[Oxidative stress, reactive oxygen species]. 1473 35

Accumulating evidence indicates that vascular dysfunction in atherosclerosis, hypertension, and diabetes is either caused by or accompanied by oxidative stress in the vessel wall. In particular, the role of redox processes as mediators of vascular repair and contributors to post-angioplasty restenosis is increasingly evident. Yet the pathophysiology of such complex phenomena is still unclear. After vascular injury, activation of enzymes such as NADPH oxidase leads to a marked increase in superoxide generation, proportional to the degree of injury, which rapidly subsides. Such early superoxide production is significantly greater after stent deployment, as compared to balloon injury. Recent data suggest the persistence of low levels of oxidant stress during the vascular repair reaction in neointimal and medial layers. Despite the compensatory increase in expression of iNOS and nNOS, nitric oxide bioavailability is reduced because of increased reaction rates with superoxide, yielding as by-products reactive nitrogen/oxygen species that induce protein nitration. Concurrently, the activity of vascular superoxide dismutases exhibits a sustained decrease following injury. This decreased activity appears to be a key contributor to vasoconstrictive remodeling and a major determinant of the occurrence of nitrative/oxidative stress. Replenishment of superoxide dismutase (SOD), as well as treatment with vitamins C and E or the lipid-lowering drug probucol and its analogs, led to decrease in constrictive remodeling and improved vessel caliber. Better understanding of the redox pathophysiology of vascular repair should help clarify the pathogenesis of many other vascular conditions and may provide novel therapeutic strategies to prevent vascular lumen loss.
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PMID:Redox processes underlying the vascular repair reaction. 1496 Nov 89

Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include beta1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, alpha-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.
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PMID:The shift in the "paradigm" of the pharmacology of hypertension. 1496 15

Accumulating evidence suggests that several polymorphisms in factors regulating blood coagulation, platelet function, and lipid metabolism are relevant for susceptibility to ischemic cerebrovascular diseases (CVD). The present study analyzed 15 genetic polymorphisms possibly associated with atherosclerosis and thrombosis in a case-control study involving a total of 200 genetically unrelated Japanese patients with ischemic CVD (mean age 58.3 +/- 7.6 y) and 281 age- and gender-matched control subjects (59.0 +/- 4.1 y). Control subjects were randomly selected from unrelated donors with no history of documented CVD or any type of cardiovascular disease with normal resting electrocardiograms. Among the factors genotyped, two factors, platelet glycoprotein (GP) Ib alpha (Thr145Met) and NADPH oxidase p22phox (His72Tyr), were significantly associated with CVD after adjustment for acquired risk factors including hypertension, diabetes mellitus, hyperlipidemia, and smoking. For those with age < 60 y, 10.6% of the CVD patients and 2.9% of the control subjects had both of the two risk genotypes (GPIb alpha 145Met and p22phox 72Tyr, p < 0.05). The mean onset-age of CVD was 58.6 +/- 7.7 y for those having no or only one risk genotype, while 53.3 +/- 5.5 y for those having both of the risk genotypes (p < 0.05). Thus, GPIb alpha 145Met and p22phox 72 Tyr are the genetic factors associated with the risk of ischemic CVD in the Japanese. Carrying both of the two mutations might be associated with developing CVD at a younger age.
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PMID:[Genetic risk factors for ischemic cerebrovascular disease--analysis on fifteen candidate prothrombotic gene polymorphisms in the Japanese population]. 1496 55

Salt-sensitive hypertension is associated with impaired NO/cGMP signaling. We hypothesized that increased superoxide production by NADPH oxidase and altered endothelial NO synthase (NOS3) phosphorylation determine endothelial dysfunction in hypertension. Experiments tested if NO/cGMP signaling and NOS3 serine phosphorylation are decreased and NADPH oxidase activity is increased in mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt rats compared with arteries from placebo rats. Concentration response curves to phenylephrine were performed in mesenteric arteries in the presence and absence of Nomega-nitro-L-arginine (LNA) and antioxidants to determine the influence of basal NO and superoxide production on vascular tone. LNA increased phenylephrine sensitivity in arteries from placebo, but not DOCA-salt rats, regardless of antioxidant treatment. To determine basal cGMP production, mesenteric arteries were incubated with 3-isobutyl-1-methylxanthine in the presence or absence of LNA, sodium nitroprusside (SNP), antioxidants, or tetrahydrobiopterin. NOS-dependent cGMP production was reduced in arteries from DOCA-salt rats compared with arteries from placebo rats and was not restored by acute treatment with antioxidants or tetrahydrobiopterin. SNP-induced cGMP production was similar between groups as was NADPH oxidase activity, measured by lucigenin chemiluminescence, in mesenteric arteries. Expression and phosphorylation of NOS3 were examined by Western blotting. Phosphorylation of NOS3 was decreased in arteries from DOCA-salt rats compared with placebo at serine residues 1179 and 635. These findings indicate that diminished NO/cGMP signaling in mesenteric arteries from DOCA-salt rats is caused by reduced phosphorylation of NOS3 at serine 1179 and serine 635, rather than NO scavenging by superoxide.
Hypertension 2004 May
PMID:Reduced NOS3 phosphorylation mediates reduced NO/cGMP signaling in mesenteric arteries of deoxycorticosterone acetate-salt hypertensive rats. 1499 98


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