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)

The purpose of this study was to investigate the effects of aspirin-like drugs on nitric oxide (NO) synthesis in rat vascular smooth muscle cells (VSMCs). We measured the accumulation of nitrite, a stable oxidation product of NO, and the expression of inducible NO synthase (iNOS) mRNA and protein in rat cultured VSMCs. Sodium salicylate, aspirin, and indomethacin dose-dependently enhanced nitrite production by interleukin (IL)-1beta-stimulated VSMCs at therapeutic plasma concentration ranges. Increased nitrite production by aspirin-like drugs was accompanied by increased iNOS mRNA and protein accumulation in VSMCs. Addition of IL-1beta activated nuclear factor kappaB (NF-kappaB) in VSMCs, but sodium salicylate did not affect IL-1beta-induced NF-kappaB activation. The nonselective lipoxygenase (LO) inhibitor nordihydroguaiaretic acid inhibited sodium salicylate-induced nitrite production, whereas the selective 5-LO inhibitor caffeic acid did not influence production of nitrite. The 12-LO product 12-HETE dose-dependently enhanced nitrite production by IL-1beta-stimulated VSMCs, whereas the 15-LO product 15-HETE did not. Our study demonstrates that aspirin and the aspirin-like drugs, sodium salicylate and indomethacin, increase NO synthesis in IL-1beta-stimulated VSMCs by upregulation of iNOS transcription via a 12-LO pathway. These effects were independent of NF-kappaB activation. In addition to the direct inhibition of platelet function, aspirin-like drugs may contribute to the reduction of atherothrombotic risk in myocardial ischemia via enhancing NO production by VSMCs.
Hypertension 2000 May
PMID:Effects of aspirin-like drugs on nitric oxide synthesis in rat vascular smooth muscle cells. 1081 69

Angiotensin II (Ang II) activates cytosolic phospholipase A(2) (cPLA(2)) and phospholipase D (PLD) in rabbit vascular smooth muscle cells (VSMCs). Ang II also activates ras/mitogen-activated protein (MAP) kinase in VSMCs; this activation is mediated by 20-hydroxyeicosatetraenoic acid (HETE) and 12(S)-HETE, which are metabolites of arachidonic acid generated by cytochrome P450 4A and lipoxygenase, respectively, produced on activation of cPLA(2). The purpose of this study was to determine if Ang II-induced PLD activation in VSMCs is mediated through the ras/extracellular signal-regulating kinase (ERK) pathway by arachidonic acid metabolites that are generated consequent to cPLA(2) stimulation. Inhibitors of PLD (C(2) ceramide), phosphatidate phosphohydrolase (propranolol), and diacylglycerol lipase (RHC 80267) attenuated Ang II-induced arachidonic acid release. Ang II-induced PLD activation, as measured by [(3)H]phosphatidylethanol production, was inhibited by C(2) ceramide but not by propranolol or RHC 80267. Ang II-induced PLD activation was decreased by the inhibitor methyl arachidonylfluorophosphate (MAFP) and the antisense oligonucleotide of cPLA(2). Inhibitors of lipoxygenases (baicalein) and cytochrome P450 4A (ODYA) attenuated Ang II-induced PLD activation. 20-HETE and 12(S)-HETE increased PLD activity. Inhibitors of ras farnesyltransferase (FPT III and BMS-191563) and MAP kinase kinase (UO126) attenuated the increase in PLD activity elicited by 20-HETE and Ang II. PLD2 was the main isoform activated by Ang II in VSMCs. These data suggest that the CYP4A metabolite 20-HETE, which is generated from arachidonic acid after cPLA(2) activation by Ang II, stimulates the ras/MAP kinase pathway, which in turn activates PLD2 and releases further arachidonic acid for prostaglandin synthesis through the phosphatidate phosphohydrolase/diacylglycerol lipase pathway.
Hypertension 2001 Feb
PMID:20-Hydroxyeicosatetraenoic acid mediates angiotensin ii-induced phospholipase d activation in vascular smooth muscle cells. 1123 Mar 46

Increased LDL oxidation is associated with coronary artery disease. The predictive value of circulating oxidized LDL is additive to the Global Risk Assessment Score for cardiovascular risk prediction based on age, gender, total and HDL cholesterol, diabetes, hypertension, and smoking. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis by stimulating monocyte infiltration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages. HDL cholesterol levels are inversely related to risk of coronary artery disease. HDL prevents atherosclerosis by reverting the stimulatory effect of oxidized LDL on monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids. Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.
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PMID:Oxidized LDL and HDL: antagonists in atherothrombosis. 1164 Dec 34

The lipoxygenase pathway has been implicated in the growth, migration, and contraction of vascular smooth muscle cells (VSMCs). However, the precise type of lipoxygenase present in the vascular wall has not been characterized. In this study, we used a specific reverse-transcriptase polymerase chain reaction method with 2 sets of specific primers on total RNA and polyA (+)RNA of normal human VSMCs prepared from umbilical artery. Two forms of platelet-type 12-lipoxygenase mRNA were present in human VSMCs: the already published form cloned from human erythroleukemia cells and a variant form of platelet-type 12-lipoxygenase, which includes 2 additional sequences consistent with the 2 introns (D and E). This novel form of 12-lipoxygenase poly A (+)RNA was downregulated by lipopolysaccharide (10 ug/ml) and upregulated by epidermal growth factor (100 ng/ml) but was not affected by angiotensin II (10(-7) mol/l). We developed a rabbit anti-human platelet-type 12-lipoxygenase polyclonal antibody directed against a 24-amino acid peptide encoded within exon 4. Western immunoblotting of protein extracted from VSMCs and umbilical artery and platelet extract with this antibody showed a coordinate 110-kDa protein and the already-described 70-kDa band detected in platelets and cord homogenate. Another 120-kDa protein was consistently detected in cord extracts but not in platelet or VSMC homogenates. The immunohistochemistry study performed with the same antibody showed extensive cytoplasmic staining of VSMCs. The specific role of these different forms of platelet-type 12-lipoxygenase is subject to further investigation.
Hypertension 2001 Oct
PMID:A novel form of platelet-type 12-lipoxygenase mRNA in human vascular smooth muscle cells. 1164

There is compelling evidence for endothelial dysfunction in both type 1 and type 2 diabetics. This dysfunction is manifest as blunting of the biologic effect of a potent endothelium-derived vasodilator, nitric oxide, and increased production of vasoconstrictors such as angiotensin II, ET-1, and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. These agents and other cytokines and growth factors whose production they stimulate cause acute increases in vascular tone, resulting in increases in blood pressure, and vascular and cardiac remodeling that contributes to the microvascular, macrovascular, and renal complications in diabetes. Reactive oxygen species, overproduced in diabetics, serve as signaling molecules that mediate many of the cellular biochemical reactions that result in these deleterious effects. Adverse vascular consequences associated with endothelial dysfunction in diabetes mellitus are Decreased nitric oxide formation, release, and action Increased formation of reactive oxygen species Decreased prostacyclin formation and release Increased formation of vasoconstrictor prostanoid Increased formation and release of ET-1 Increased lipid oxidation Increased cytokine and growth factor production Increased adhesion molecule expression Hypertension Changes in heart and vessel wall structure Acceleration of the atherosclerotic process Treatment with antioxidants and with inhibitors of the renin-angiotensin system may reverse some of the pathologic vascular changes associated with endothelial dysfunction.
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PMID:Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. 1172 7

Have studied action of chronic urea--an arginase inhibitor--introduction (40 mg/kg, 28 days) on blood pressure, endothelium-dependent reactions of aorta smooth muscle cells (SMC) and nonenzymatic (contents of diene conjugates and H2O2) and enzymatic (contents of free arachidonic acid and vasoconstrictic eicosanoids LTC4 and TXA2) oxidizing lipid metabolism of heart, aorta, plasma and erythrocytes of spontaneously hypertensive rats. Have shown, that urea down regulate blood pressure without any normalization of endothelium-dependent reactions of SMC of aorta and down regulate both enzymatic and nonenzymatic oxidizing lipid metabolism. Down regulation of two alternative (by cyclooxygenase and by lipoxygenase) enzymatic pathways of free arachidonic acid oxidizing metabolism by urea can be one of mechanisms of its antihypertensive action. The possibility of urea use at hypertension and various pathophysiological conditions are discussed.
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PMID:[Inhibitors of arginase in the L-arginine metabolic pathway as a new class of antihypertensive drugs: effect of carbamide on lipid oxidative metabolism and on vessel tonus during arterial hypertension]. 1175 64

Nitric oxide (NO) is a major free radical modulator of smooth muscle tone, which under basal conditions acts to preserve vascular homeostasis through its anti-inflammatory properties. The biochemistry of NO, in particular, its rapid conversion in vivo into secondary reactive nitrogen species (RNS), its chemical nature as a free radical and its high diffusibility and hydrophobicity dictate that this species will interact with numerous biomolecules and enzymes. In this review, we consider the interactions of a number of enzymes found in the vasculature with NO and NO-derived RNS. All these enzymes are either homeostatic or promote the development of atherosclerosis and hypertension. Therefore their interactions with NO and NO-derived RNS will be of central importance in the initiation and progression of vascular disease. In some examples, (e.g. lipoxygenase, LOX), such interactions provide catalytic 'sinks' for NO, but for others, in particular peroxidases and prostaglandin H synthase (PGHS), reactions with NO may be detrimental. Nitric oxide and NO-derived RNS directly modulate the activity of vascular peroxidases and LOXs through a combination of effects, including transcriptional regulation, altering substrate availability, and direct reaction with enzyme turnover intermediates. Therefore, these interactions will have two major consequences: (i) depletion of NO levels available to cause vasorelaxation and prevent leukocyte/platelet adhesion and (ii) modulation of activity of the target enzymes, thereby altering the generation of bioactive signaling molecules involved in maintenance of vascular homeostasis, including prostaglandins and leukotrienes.
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PMID:Interactions of nitric oxide-derived reactive nitrogen species with peroxidases and lipoxygenases. 1176 4

We have reported that norepinephrine (NE) and angiotensin II (Ang II) increase CaM kinase II activity, which, in turn, activates cytosolic phospholipase A(2) (PLA(2)) and releases arachidonic acid. The products of arachidonic acid generated via cytochrome P-450 and lipoxygenase contribute to the development of hypertension and vascular smooth muscle cell (VSMC) hyperplasia. The purpose of this study was to investigate whether CaM kinase II contributes to VSMC proliferation elicited by NE and Ang II and to hypertension induced by Ang II. NE (1 micromol/L) and Ang II (1 micromol/L) increased proliferation of rabbit aortic VSMC as measured by increased [(3)H]-thymidine incorporation; this effect of NE and Ang II was attenuated 88 +/- 10% and 64 +/- 11% by the CaM kinase II inhibitor KN-93, respectively. Infusion of Ang II with miniosmotic pumps (350 ng/min for 6 days) in rats elevated mean arterial pressure (MABP), which was reduced by simultaneous infusion of KN-93 (578 ng/min, for 6 days) (Ang II alone: MABP =174 +/- 3 mm Hg, n=12 versus Ang II + KN-93: MABP 123 +/- 5 mm Hg, n=4, P<0.05). Administration of KN-93 as a single bolus injection (16 mg/Kg), but not its vehicle, in Ang II--infused hypertensive animals also decreased MABP from 179 +/- 9 mm Hg to 109 +/- 6 mm Hg (n=5, P<0.05). CaM kinase II activity was increased in the kidney of Ang II--infused hypertensive animals compared with normotensive controls. Treatment with KN-93 reduced CaM kinase II activity and ameliorated the intravascular injury in the kidneys of Ang II--infused hypertensive rats. Our data indicate that CaM kinase activation represents an important component of the mechanism(s) initiating VSMC proliferation and the development and maintenance of Ang II--induced hypertension in rat.
Hypertension 2002 Feb
PMID:Functional significance of activation of calcium/calmodulin-dependent protein kinase II in angiotensin II--induced vascular hyperplasia and hypertension. 1188 35

Arachidonic acid metabolism-derived products are key mediators of angiotensin II-mediated vascular effects. The modulatory effect of cyclooxygenase derived products--in particular thromboxane A2 and prostaglandin H2--in angiotensin II-mediated vascular effects is well established. In contrast, few studies have assessed the involvement of lipoxygenase-derived products in the vascular effects of angiotensin II. Cysteinyl leukotrienes (5-lipoxygenase-derived products) and 12-hydroxyeicosatetraenoic acids (12-HETE) (12-lipoxygenase-derived products) are potent proinflammatory and vasomotor mediators. Their biosynthesis is increased in various models of hypertension. In addition, compelling evidence has suggested that they might contribute to the vasoconstrictor, hypertrophic and mitogenic effects of angiotensin II. The demonstration of their contribution to angiotensin II-mediated vascular effects may explain, at least in part, the vascular inflammatory complications associated with hypertension.
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PMID:[Leukotrienes and 12-HETE: key mediators of angiotensin II-mediated vascular effects.Rol in hypertension]. 1218 63

Based on the clinical observation that humans with visceral adiposity have higher plasma aldosterone levels than controls, we postulated that endogenous fatty acids can be oxidized by the liver to form stimuli of the adrenal cortex. Although we could show that hepatocytes produced adrenal stimuli from linoleic acid in vitro, the yield was very small. To facilitate the elucidation of chemical structures, we incubated a large amount of linoleic acid with lipoxygenase, then treated the hydroperoxide with cysteine and iron. The major product of this process was 12,13-epoxy-9-keto-10-trans-octadecenoic acid. This epoxy-keto compound stimulated aldosterone production at concentrations from 0.5 to 15 microm. At higher concentrations, it was inhibitory. The epoxy-keto-octadecenoic acid exhibited the chromatographic characteristics of one product of the incubation of linoleic acid with hepatocytes. The results are consistent with the postulated conversion of linoleic acid to stimuli of aldosterone production. This may be a mechanistic link between visceral obesity and hypertension in humans.
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PMID:An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro. 1232 36


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