Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In hypertension, increased peripheral resistance maintains elevated levels of arterial blood pressure. The increase in peripheral resistance results, in part, from abnormal constrictor and dilator responses and vascular remodeling. In this review, we consider four cellular signaling pathways as possible explanations for these abnormal vascular responses: (1) augmented signaling via the epidermal growth factor receptor to cause remodeling of the cerebrovasculature; (2) reduced sphingolipid signaling leading to blunted vasodilation and increased smooth muscle proliferation; (3) increased signaling via Rho/Rho kinase leading to enhanced vasoconstriction, and (4) a relative state of microtubular depolymerization favoring vasoconstriction in hypertension. These novel cell signaling pathways provide new pharmacological targets to reduce total peripheral vascular resistance in hypertension.
 ...
PMID:Novel signaling pathways contributing to vascular changes in hypertension. 1106 Apr 92

Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1ss (IL-1ss)-induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10(-)(8) to 10(-)(5) mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1ss induced nuclear factor-kappaB activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1ss-induced nitrite accumulation in VSMCs. These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.
Hypertension 2000 Dec
PMID:Fluvastatin upregulates inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells. 1111 1

Hypercontraction or abnormal contraction of vascular smooth muscle is a major cause of diseases such as hypertension and vasospasm of the coronary and cerebral arteries. A better understanding of the mechanism of regulation of smooth muscle contraction should lead to improved treatments for such diseases. Recent studies have revealed important roles for the small GTPase Rho and its effector, Rho-associated kinase (Rho kinase) in Ca2+ independent regulation of smooth muscle contraction. The Rho-Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain of myosin II, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca2+ sensitization in smooth muscle contraction. Rho-Rho-kinase mechanisms also participate in a variety of the cellular functions of non-muscle cells, such as stress-fibre formation, cytokinesis and cell migration. This review summarizes the role of the Rho-Rho-kinase pathway in contractile processes of smooth muscle and in non-muscle cell functions, and the pathophysiological implications of this pathway.
 ...
PMID:Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. 1116 70

Angiotensin II (Ang II)-induced phospholipase D (PLD) activity is greater in aortic smooth muscle from spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto rats (WKY). Whether and how this signaling pathway is altered in preglomerular microvascular smooth muscle cells (PGSMCs), a cell type that may participate in genetic hypertension, is unknown. The goals of the present study were to determine in SHR and WKY PGSMCs the following: (1) whether Ang II induces PLD activity; (2) whether the effect of Ang II on PLD activity is greater in SHR; (3) which PLD isoform is stimulated by Ang II; (4) what signaling pathway mediates Ang II-induced PLD stimulation; and (5) whether the signaling pathways mediating Ang II-induced PLD activity are different in SHR and WKY. The EC(50) for Ang II-induced PLD stimulation in SHR was 10-fold lower than the EC(50) in WKY, and both were inhibited by L-158,805, an AT(1) antagonist. Inhibitors of phosphoinositol-3-kinase and protein kinase C did not block Ang II-induced PLD activity in SHR and WKY PGSMCs. Catalytically-inactive constructs of PLD2 and RhoA, but not PLD1, ADP ribosylation factor 1 (ARF1), ARF6, or ADP ribosylation factor nucleotide exchange factor (ARNO) blocked Ang II-induced PLD activity in SHR and WKY PGSMCs. Brefeldin A completely blocked Ang II-induced PLD activity in SHR but only slightly reduced Ang II-induced PLD activity in WKY PGSMCs. Therefore, we conclude that in PGSMCs, the effect of Ang II on PLD activity is (1) greater in SHR; (2) mediated by AT(1) receptors signaling to PLD2; (3) transduced primarily by Rho proteins; and (4) inhibited in SHR by brefeldin A.
Hypertension 2001 Feb
PMID:Angiotensin II signaling to phospholipase D in renal microvascular smooth muscle cells in SHR. 1123 Mar 48

Rho-like small GTPases, with their main representatives (Rho, Rac, and Cdc42), have been recognized in the past decade as key regulators of the F-actin cytoskeleton. Rho-like small GTPases are now known to play a major role in vascular processes caused by changes in the actin cytoskeleton, such as smooth muscle cell contraction, endothelial permeability, platelet activation, and leukocyte migration. Data are now accumulating regarding the involvement of Rho GTPases in vascular disorders associated with vascular remodeling, altered cell contractility, and cell migration. The unraveling of signal transduction pathways used by the Rho-like GTPases revealed many upstream regulators and downstream effector molecules, and their number is still growing. An important action of Rho, Rac, and Cdc42 is their ability to regulate the phosphorylation status of the myosin light chain, a major regulator of actin-myosin interaction. Present knowledge of the Rho-like small GTPases has resulted in the development of promising new strategies for the treatment of many vascular disorders, including hypertension, vasospasms, and vascular leakage.
 ...
PMID:Cytoskeletal effects of rho-like small guanine nucleotide-binding proteins in the vascular system. 1123 7

Hypertension, the result of a sustained increase in vascular peripheral resistance, is partly due to vascular remodeling and increased vasoconstrictor sensitivity. Stimulation of heterotrimeric G-protein-coupled receptors by various contractile agonists activates intracellular signaling molecules to result in an increase in cytosolic Ca++ and the subsequent phosphorylation of myosin light chain by Ca++/calmodulin-dependent myosin light chain kinase. Additionally, a portion of alpha-adrenergic, serotonergic, and endothelin-1-induced contraction is partially mediated by the calcium-independent activation of the small G-protein RhoA and of a downstream target, Rho-kinase. Isolated arteries from hypertensive animals have been shown to have an increased contractile sensitivity to various agonists and to exhibit evidence of remodeling. Recent data suggest that some of these vascular changes may be mediated by increased activity of RhoA/Rho-kinase, potentially introducing a novel therapeutic approach for the treatment of hypertension.
 ...
PMID:RhoA/Rho-kinase, vascular changes, and hypertension. 1127 96

The small G protein Rho and its target Rho-kinase may participate in the mechanisms underlying vascular contractile tone via inhibition of myosin light chain phosphatase. The present study has tested the hypothesis that Rho-kinase activity normally contributes to cerebral vascular tone in vivo, and that this effect is augmented during chronic hypertension. Comparative studies also examined the role of protein kinase C (PKC) in regulation of cerebral artery tone. Two Rho-kinase inhibitors, Y-27632 (0.1 to 100 micromol/L) and HA1077 (1 to 10 micromol/L), caused marked concentration-dependent increases in basilar artery diameter of anesthetized normotensive rats (Sprague-Dawley and Wistar-Kyoto [WKY] strains), as measured using a cranial window approach. By comparison, the selective PKC inhibitors calphostin C (0.01 to 0.5 micromol/L) and Ro 31-8220 (5 micromol/L) had little or no effect on basilar artery diameter. Vasodilator responses to Y-27632 were unaffected by PKC inhibition or activation. In two models of chronic hypertension (spontaneously hypertensive rats and WKY rats treated with N-nitro-L-arginine methyl ester for 4 weeks), Y-27632 elicited cerebral vasodilator responses that were significantly greater than in control WKY rats (P<0.05), indicating that the chronically hypertensive state and not genetic factors contributed to the increased responses to Rho-kinase inhibition. PKC inhibition had no significant effect on basilar artery diameter in chronically hypertensive rats. These data suggest that Rho-kinase, but not PKC, activity contributes substantially to cerebral artery tone in vivo, and this effect is augmented in the cerebral circulation during chronic hypertension.
 ...
PMID:Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C. 1132 68

Plasminogen activator inhibitor type-1 (PAI-1) plays an integral role not only in the regulation of fibrinolytic activity but also in the pathogenesis of atherosclerosis and hypertension. We investigated the signaling pathways of angiotensin II (Ang II) leading to PAI-1 gene expression. Ang II increased the PAI-1 mRNA and protein levels in a time- and dose-dependent manner through the Ang II type 1 receptor in vascular smooth muscle cells. PAI-1 gene promoter activity measured by luciferase assay was significantly increased by Ang II. PAI-1 mRNA stability was also increased by Ang II. Ang II-induced PAI-1 mRNA upregulation was inhibited by BAPTA-AM, genistein, and AG1478, suggesting that intracellular calcium, tyrosine kinase, and epidermal growth factor receptor transactivation are involved. Furthermore, PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) kinase (MEK), almost completely suppressed Ang II-induced PAI-1 upregulation. Adenovirus-mediated overexpression of the dominant-negative form of Rho-kinase or Y27632, a Rho-kinase inhibitor, also completely prevented PAI-1 induction by Ang II without affecting Ang II-induced ERK activation. These data suggest that activation of MEK/ERK and Rho-kinase pathways plays a pivotal role in PAI-1 gene upregulation by Ang II. The Rho-kinase pathway may be a novel target to inhibit Ang II signaling, and its inhibition may be useful in the treatment of hypertension as well as atherosclerosis.
 ...
PMID:Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. 1134 89

Recently, it was shown that Rho-kinase plays an important role in blood pressure regulation. However, it is not known whether Rho-kinase is involved in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine that regulates monocyte recruitment and atherogenesis. Therefore, we examined the role of Rho and Rho-kinase in the angiotensin (Ang) II-induced expression of MCP-1. Ang II dose- and time-dependently enhanced the expression of MCP-1 mRNA and the protein production in vascular smooth muscle cells. CV11974, an Ang II type 1 receptor (AT(1)-R) specific antagonist inhibited the enhancement of MCP-1 expression by Ang II, suggesting that the effect of Ang II is mediated by the AT(1)-R. Botulinum C3 exotoxin, a specific inhibitor of Rho, suppressed Ang II-induced MCP-1 production. To examine the role of Rho-kinase in Ang II-induced MCP-1 expression, we used adenovirus-mediated overexpression of the dominant negative mutant of Rho-kinase (AdDNRhoK) or Y-27632, a specific inhibitor of Rho-kinase. Both AdDNRhoK and Y-27632 strongly inhibited Ang II-induced MCP-1 expression. Although inhibition of extracellular signal-regulated protein kinase (ERK) by PD 098,059 also inhibited Ang II-induced MCP-1 expression, Y-27632 did not affect Ang II-induced activation of ERK. These results indicate that Rho-kinase plays a critical role in Ang II-induced MCP-1 production independent of ERK. The Rho-Rho-kinase pathway may be a novel target for the inhibition of Ang II signaling and the treatment of atherosclerosis.
Hypertension 2001 Jul
PMID:Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. 1146 68

We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was approximately 2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[(35)S]GTPgammaS binding. RhoA protein and activity were also increased in vessels from rats treated with N-nitro-L-arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27(Kip1) was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27(Kip1) induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110(CAAX)]) decreased p27(Kip1) expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27(Kip1), mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.
 ...
PMID:Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats. 1155 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>