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)

Long-acting dihydropyridine calcium channel blockades have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events in humans and animals. To investigate the vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (20 mg/kg/ day) and manidipine (10 mg/kg/day) were administered by gavage to N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats for 2 weeks. L-NAME treatment (0.7 mg/ml in drinking water) significantly decreased the gene and protein expression of endothelial nitric oxide synthase (eNOS) and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in the aorta, as determined by Western blotting and reverse transcription (RT)-polymerase chain reaction (PCR). Amlodipine and manidipine normalized the decreased expression of eNOS gene and protein, and attenuated the overexpression of NADPH oxidase, VCAM-1, and MCP-1 mRNA. Furthermore, amlodipine and manidipine prevented the L-NAME-induced increase in the angiotensin converting enzyme (ACE) mRNA content, thereby restoring control levels in the aorta. On the other hand, hydralazine treatment had no such effect in L-NAME treated rats. Furthermore, the increased expression of manganese superoxide dismutase (Mn-SOD) by L-NAME treatment was not affected by amlodipine, manidipine, or hydralazine. We concluded that the direct anti-inflammatory and antioxidative effects of calcium channel blockades in the aorta of rats with L-NAME-induced hypertension were not likely to have been mediated by the blood pressure-lowering action of these agents, but instead these beneficial effects appear to have been mediated by an augmentation of eNOS expression and by the inhibition of the expression of ACE.
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PMID:Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of endothelial nitric oxide synthase and the inhibition of angiotensin converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood pressure-lowering effects of amlodipine and manidipine. 1639 74

We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) alpha contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-alpha blocker, etanercept. Arterial pressure increased from 94+/-5 to 148+/-7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90+/-2 to 109+/-6 mm Hg). After 2 weeks, arterial pressure increased to 156+/-11 mm Hg in the angiotensin high-salt group and 141+/-6 mm Hg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275+/-47 versus 81+/-19 ng/day) and was decreased in the etanercept-treated group (153+/-31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-alpha contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.
Hypertension 2006 Mar
PMID:Tumor necrosis factor alpha blockade increases renal Cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension. 1641 73

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor kappaB (NF-kappaB) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-alpha-induced NF-kappaB activation and TNF-alpha-induced IkappaB kinase activity. Furthermore, metformin attenuated the TNF-alpha-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-alpha- and interleukin-1beta-induced NF-kappaB reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1beta-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-kappaB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.
Hypertension 2006 Jun
PMID:Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. 1663 95

Investigators have suggested that inflammation may play a role in the pathogenesis of valve calcium. Participants in the Framingham Heart Study's offspring cohort had systemic levels of C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and monocyte chemoattractant protein-1 measured at examination cycle 7. Mitral annular calcium, aortic annular calcium, aortic sclerosis, and aortic stenosis were assessed by echocardiography at examination cycle 6. Logistic regression was used to examine the odds of valvular calcium per 1 unit increase in inflammation (ISUM), a summary statistic of all normalized deviates of the individual markers. Two thousand six hundred eighty-three participants (mean age 61 +/- 10 years; 52% women) were analyzed: 8.2% (n = 216) had > or = 1 calcified valve or annulus; 89 had mitral annular calcium, 78 had aortic annular calcium, 135 had aortic sclerosis, and 33 had aortic stenosis. Participants with valvular calcium were older and were more likely to have hypertension and diabetes mellitus. Participants with valve calcium had higher median levels of all markers. For each log unit increase in ISUM, after adjustment for age and gender, there was an associated 1.1-fold increased odds of > or = 1 calcified valve (p = 0.02); the odds ratios were no longer significant after adjustment for cardiovascular disease risk factors (odds ratio 1.0, 95% confidence interval 0.9 to 1.1). Similar results were obtained for the individual markers and the odds of > or = 1 calcified valve. In conclusion, inflammatory markers were elevated in patients with valvular calcium. Our findings suggest that much of the observed association between systemic inflammatory markers and valvular calcium may be due to shared risk factors.
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PMID:Relations of inflammation and novel risk factors to valvular calcification. 1667 93

It has not been completely demonstrated if hypertension may, in part, develop as a result of increased oxidative stress (OS), inflammation and little is known about the short-term effects of antioxidant therapy. This study was designed to appreciate the effect of 7 days vitamin C-enriched diet (5 g/kg/day) on hemodynamic function and vascular OS in normotensive Wistar Kyoto rats and hypertensive rats (SHR). Aorta NAD(P)H oxidase activity was determinate and free radicals evaluated by electron spin resonance with a spin probe CP-H. Matrix metalloproteinase-1 (MMP-1) and monocyte chemoattractant protein-1 (MCP-1) expression were measured. The treatment with vitamin C did not change arterial pressure in SHR but prevented the increase in OS levels in SHR aortas. MMP-1 and MCP-1 expressions were more intense in the media of SHR aortas than in those of WKY rats but these expressions were not modified by vitamin C-pretreatment. Vitamin C-pretreatment was not able to protect heart against in vitro ischemia-reperfusion dysfunctions. These data may suggest that treatment with high doses of vitamin C in SHR can limit over-production of reactive oxygen species; however this effect was not accompanied with changes in arterial pressure and protection against I-R dysfunctions. Dissociation between vascular oxidative stress and cardiovascular function may be evoked.
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PMID:Dissociation between vascular oxidative stress and cardiovascular function in Wistar Kyoto and spontaneously hypertensive rats. 1676 52

Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-beta pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n = 9); aldosterone (0.75 microg/h, subcutaneously; n = 9); or aldosterone + fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n = 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in alpha-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased alpha-smooth muscle actin staining, numbers of monocytes/macrophages, mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor and monocyte chemoattractant protein-1, and Smad2/3 activity in renal cortical tissues. These results provide evidence, for the first time, that Rho-kinase is substantially involved in aldosterone-induced renal injury through activation of a TGF-beta-dependent pathway.
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PMID:Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury. 1679 May 7

Obesity has been linked to cardiovascular disease, hypertension, diabetes and the metabolic syndrome, with elevated markers of systemic inflammation. Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane adhesion molecule involved in leukocyte migration to sites of inflammation. In human obesity, elevated expression of the soluble form of ICAM-1 (sICAM-1) is positively correlated with abdominal fat deposition. Increases in adiposity have also been correlated with macrophage infiltration into adipose tissue. Here we investigate adipose tissue production and transcriptional regulation of ICAM-1 in a mouse model of dietary obesity. After feeding mice a high-fat diet, ICAM-1 expression in serum and adipose tissue was analyzed by ELISA, Northern blotting, real-time quantitative PCR, and flow cytometry. After 6 mo on the high-fat diet, sICAM-1 levels significantly correlated with body weight and abdominal fat mass. ICAM-1 mRNA was expressed in adipose tissue of mice, with significantly higher levels in males than females. After only 3 wk, there were adipose tissue-specific increases in mRNAs for ICAM-1, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in male mice. Analysis of the stromal-vascular fraction of male adipose tissue revealed CD11b-negative cells with increased surface ICAM-1 and CD34. We also found two populations of F4/80+, CD11b+, ICAM-1+ cells, one of which also expressed CD14 and CD11c and was increased in response to a high-fat diet. These results indicate that within 3 wk on a high-fat diet, male mice exhibited significant increases in pro-inflammatory factors and immune cell infiltration in adipose tissue that may represent links between obesity and its associated inflammatory complications.
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PMID:ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice. 1680 3

The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by approximately 30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker.
Hypertension 2006 Oct
PMID:Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells. 1694 Feb 31

The authors have previously shown that arterial wall strain mediates the development of vessel wall inflammation in experimental hypertension. The current studies explore the mechanoregulation of monocyte chemoattractant protein-1 (MCP-1), a potent pro-inflammatory chemokine, by mitogen-activated protein kinases (MAPK) and oxidative stress. Rat aortic smooth muscle (RASM) cells were subjected to cyclic strain on a uniform biaxial strain device. Strain rapidly activated both ERK1/2(MAPK) and p38(MAPK), with peak activation at 5 min. Strain induced a twofold increase in MCP-1 mRNA, which was attenuated by PD 98059, a specific ERK1/2(MAPK) inhibitor, and SB 203580, a specific p38(MAPK) inhibitor. Cyclic strain also increased production of superoxide anion via an NADPH oxidase-dependent mechanism. To assess the potential role of reactive oxygen species in MAPK activation, cells were stretched in the presence of N-acetylcysteine, which had no effect on p38(MAPK) activation, but significantly inhibited ERK1/2(MAPK) activation and MCP-1 expression. In conclusion, redox-sensitive activation of ERK1/2(MAPK) and redox-insensitive activation of p38(MAPK) regulate straininduced MCP-1 expression in RASM cells. These findings define a role for MAPK signal transduction in establishing a pro-inflammatory state in the arterial wall, and thus implicate a potential molecular link between arterial wall strain and atherosclerosis.
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PMID:Mechanoregulation of monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. 1698 3

Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.
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PMID:Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II. 1724 18


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