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)

Under normal conditions, contractile activity in vascular smooth muscle is initiated by either receptor activation (norepinephrine, angiotensin II, etc.) or by a stretch-activated mechanism. After this activation, several signaling pathways can initiate a Ca2+-calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca2+ sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase thereby maintaining force generation. In opposition to force generation, NO is released from endothelial cells and causes vasodilation through inhibition of the RhoA/Rho-kinase signaling pathway. This brief review will highlight recent studies demonstrating a role for the RhoA/Rho-kinase signaling pathway in the increased vasoconstriction characteristic of hypertension.
Hypertension 2004 Dec
PMID:Hypertension and RhoA/Rho-kinase signaling in the vasculature: highlights from the recent literature. 1552 Mar 2

ANG II activation of phospholipase D (PLD) is required for ERK and NAD(P)H oxidase activation, both of which are involved in hypertension. Previous findings demonstrate that ANG II stimulates PLD activity through AT(1) receptors in a RhoA-dependent mechanism. Additionally, endogenous AT(2) receptors in preglomerular smooth muscle cells attenuate ANG II-mediated PLD activity. In the present study, we examined the signal transduction mechanisms used by endogenous AT(2) receptors to modulate ANG II-induced PLD activity through either PLA(2) generation of lysophosphatidylethanolamine or Galpha(i)-mediated generation of nitric oxide (NO) and interaction with RhoA. Blockade of AT(2) receptors, Galpha(i) and NO synthase, but not PLA(2), enhanced ANG II-mediated PLD activity in cells rich in, but not poor in, AT(2) receptors. Moreover, NO donors, a direct activator of guanylyl cyclase and a cGMP analog, but not lysophosphatidylethanolamine, inhibited ANG II-mediated PLD activity, whereas an inhibitor of guanylyl cyclase augmented ANG II-induced PLD activity. AT(2) receptor- and NO-mediated attenuation of ANG II-induced PLD activity was completely lost in cells transfected with S188A RhoA, which cannot be phosphorylated on serine 188. Therefore, our data indicate that AT(2) receptors activate Galpha(i), subsequently stimulating NO synthase and leading to increased soluble guanylyl cyclase activity, generation of cGMP, and activation of a protein kinase, resulting in phosphorylation of RhoA on serine 188. Furthermore, because AT(2) receptors inhibit AT(1) receptor signaling to PLD via modulating RhoA activity, AT(2) receptor signaling can potentially regulate multiple vasoconstrictive signaling systems through inactivating RhoA.
 ...
PMID:AT2 receptors cross talk with AT1 receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity. 1557 19

Hypertension is a cardiovascular disorder characterized by increased peripheral vascular resistance and/or vascular structural remodeling. Recently, rapidly growing evidence from hypertensive animal models suggests that small GTPase Rho and its downstream effector, Rho-kinase, play an important role in the pathogenesis of hypertension. Activation of the Rho/Rho-kinase pathway is essential for smooth muscle contractility in hypertension. A greater RhoA expression and an enhanced RhoA activity have been observed in aortas of hypertensive rats, such as genetic spontaneously hypertensive rats and N(omega)-nitro-L-arginine methyl ester-induced hypertension. The enhanced RhoA expression and activity was already observed in young spontaneously hypertensive rats before the onset of hypertension. These results suggest that both genetic factors and blood pressure can upregulate RhoA expression. Moreover, Y-27632 or fasudil, the specific Rho-kinase inhibitors, markedly decreased blood pressure in various hypertensive model rats, but did not in normotensive animals. In addition, Rho-kinase inhibitors have been shown to inhibit hypertensive vascular lesion formation. Therefore, Rho-kinase inhibitors may have a therapeutic potential for the treatment of hypertensive patients.
 ...
PMID:Rho-kinase, a potential therapeutic target for the treatment of hypertension. 1560 12

Lowering blood pressure using thiazide-like diuretics, including chlorthalidone and hydrochlorothiazide, has been proven to be effective in clinical studies. However, the mechanisms by which thiazide-like diuretics lower blood pressure are still poorly understood. To evaluate whether thiazide-like diuretics cause calcium desensitization in smooth muscle cells, we measured their effects on agonist-induced increase of blood pressure in Wistar rats in vivo and on agonist-induced vasoconstriction of aortic rings, DNA synthesis, and protein synthesis, RhoA, Rho kinase, and intracellular calcium in vascular smooth muscle cells in vitro. Thiazide-like diuretics significantly attenuated angiotensin II-induced or norepinephrine-induced increase of systolic blood pressure in rats. Thiazide-like diuretics inhibited agonist-induced vasoconstriction of aortic rings in a concentration-dependent manner in the presence and absence of endothelium. The inhibitory effects of thiazide-like diuretics were similar to that of the specific Rho kinase inhibitor Y27632. RT-PCR and immunoblotting showed that RhoA and Rho kinase were significantly reduced in vascular smooth muscle cells after administration of thiazide-like diuretics. In contrast, thiazide-like diuretics did not affect protein tyrosine phosphatase-2 (SHP-2) expression. Agonist-induced changes of intracellular calcium were not affected by thiazide-like diuretics. The study indicates that thiazide-like diuretics inhibit agonist-induced vasoconstriction by calcium desensitization in smooth muscle cells linked to the Rho-Rho kinase pathway.
Hypertension 2005 Feb
PMID:Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase. 1561 60

Resistance arteries are able to adapt to physiological and pathophysiological stimuli to maintain adequate perfusion according to the metabolic demand of the tissue. Although vasomotor control allows rapid adaptation of lumen diameter, vascular remodeling constitutes an active process that occurs in response to long-term alterations of hemodynamic parameters. Unfortunately, this initially adaptive process contributes to the pathology of vascular diseases. Recent studies have demonstrated the participation of Rho protein signaling pathways in several cardiovascular pathologies including hypertension, coronary artery spasm, effort angina, atherosclerosis, and restenosis. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration, and proliferation associated with arterial diseases. The present review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in resistance artery remodeling, more particularly in relation to hypertension.
 ...
PMID:RhoA and resistance artery remodeling. 1570 42

RhoA and Rho-kinase (ROCK) participate in a wide variety of cell signal functions such as cell growth, smooth and cardiac muscle contraction, cytoskeleton rearrangement, cell migration and proliferation. In vascular smooth muscle cells, RhoA and ROCK play an important role in Ca2+ sensitization and regulate vascular smooth muscle tone. In the heart, RhoA and ROCK mediate hypertrophic response leading to cardiac hypertrophy. Recent cellular and molecular biology studies using ROCK inhibitors such as Y-27632 and fasudil have indicated a pivotal role of the RhoA-ROCK cascade in many aspects of cardiovascular function such as cardiac hypertrophy and ventricular remodeling following myocardial infarction. Inhibition of the RhoA-ROCK signaling pathway may be a suitable target for a number of cardiovascular diseases including hypertension, atherosclerosis, diabetes and hypertrophic heart failure. This review focuses on the current understanding of the RhoA-ROCK signal pathway in heart diseases and discusses the use of ROCK inhibitors as therapeutic agents for heart diseases ranging from hypertensive cardiomyopathy to heart failure.
 ...
PMID:Small guanine nucleotide-binding protein Rho and myocardial function. 1571 22

Vascular smooth muscle cells (VSMCs) have a remarkable degree of plasticity and in response to vascular injury, they can change to a dedifferentiated state that can be typically seen in cell cultures. Recently, Y27632, a Rho kinase inhibitor, has been reported to preferentially correct hypertension in a hypertensive rat model. We thus tested the hypothesis that the contraction of the cultured VSMCs might be more dependent on the function of RhoA than the VSMCs in fresh tissue. For this purpose, a tissue-like ring preparation was made using the cultured porcine coronary artery SMCs (CASMCs) and collagen gel (reconstituted ring: R-ring). The R-ring developed an isometric tension on stimulation by high external K+ or various receptor agonists. The phorbol ester (a protein kinase C (PKC) activator)-induced contraction of the intact R-ring was greatly inhibited, while the GTPgammaS (an activator of RhoA)-induced and Ca2+-independent contraction of permeabilized R-ring was greatly enhanced, in comparison to the fresh coronary artery ring. An immunoblot analysis showed the expression levels of RhoA and myosin phosphatase subunits (MYPT1 and PP1cdelta) to be up-regulated, while the levels of CPI-17 (PKC-potentiated protein phosphatase-1 inhibitory protein), h1-calponin and PKC isoforms were downregulated in cultured CASMCs. The knock down of RhoA by RNA interference decreased the contractility of the cultured CASMCs. It is concluded that the contractility of the cultured VSMCs thus appears to be much more dependent on the function of RhoA than VSMCs in fresh tissue. The expression level of RhoA thus plays a crucial role in regulating the contractility of cultured VSMCs.
 ...
PMID:Contractile properties of the cultured vascular smooth muscle cells: the crucial role played by RhoA in the regulation of contractility. 1577 57

As the cellular and molecular mechanisms of major arterial diseases such as atherosclerosis and hypertension are being more clearly defined, it is becoming apparent that these pathological processes share a number of functional and biochemical features in the vessel wall. Typically, arterial diseases are associated with functional and structural wall alterations including modified contractile properties, smooth muscle cell hypertrophy and proliferation, endothelial dysfunction, excessive extracellular matrix accumulation and inflammation. Small G proteins of the Rho family are defined as major regulators of cell functions including migration, proliferation, differentiation and gene transcription. Recent studies have demonstrated that activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration and proliferation associated with arterial diseases. This review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in vascular diseases.
 ...
PMID:Rho proteins and vascular diseases. 1581 29

Myogenic tone (MT), a fundamental stretch-sensitive vasoconstrictor property of resistance arteries and veins, is a key determinant of local blood flow regulation. We evaluated the pathways involved in MT development. The role of the RhoA/Rho kinase, p38 MAP kinase, and HSP27 in MT was investigated in the rabbit facial vein (RFV), previously shown to possess MT at a pressure level equivalent to 20 mm Hg. Venous MT is poorly understood, although venous diseases affect a large proportion of the population. Stretched RFV are characterized by a temperature-sensitive MT, which is normal at 39 degrees C but fails to develop at 33 degrees C. This allows for the discrimination of the pathways involved in MT from the multiple pathways activated by stretch. Isolated RFV segments were mounted in organ baths and stretched. Temperature was then set at 33 degrees C or 39 degrees C. MT was associated to the translocation of RhoA to the plasma membrane and the Rho kinase inhibitor Y27632 decreased stretch-induced MT by 93.1+/-4.9%. MT was also associated to an increase in p38 (131.0+/-12.5% at 39 degrees C versus 100% at 33 degrees C) and HSP27 phosphorylation (196.1+/-13.3% versus 100%), and the p38 MAP kinase inhibitor SB203580 decreased MT by 36.5+/-8.1%. (39 degrees C, compared with RFV stretched at 33 degrees C). Finally, phosphorylation of p38 was blocked by Y27632 and HSP27 phosphorylation was inhibited by SB203580 and Y27632. Thus, MT and the associated p38 and HSP27 phosphorylation seem to depend on RhoA/Rho kinase activation in stretch RFV.
Hypertension 2005 May
PMID:Involvement of RhoA/Rho kinase pathway in myogenic tone in the rabbit facial vein. 1583 33

Resistance arteries undergo structural changes (vascular remodelling) in hypertension. These changes involve media thickening, reduced lumen diameter and consequent increased media:lumen ratio. Cellular processes underlying these events include altered vascular smooth muscle cell (VSMC) growth, migration, differentiation and increased extracellular matrix abundance. Another factor contributing to remodelling is inflammation, associated with macrophage infiltration, fibrosis and increased expression of redox-sensitive pro-inflammatory genes. Among the factors involved in arterial remodelling, angiotensin (Ang) II appears to be one of the most important. Ang II, a multifunctional peptide with pleiotropic actions, modulates vasomotor tone, cell growth, apoptosis/anoikis, cell migration and extracellular matrix deposition. It is pro-inflammatory and it stimulates production of growth factors and vasoactive agents. The multiple actions of Ang II are mediated via complex intracellular signalling pathways including stimulation of the phosholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3)-1,2-diacylglycerol (DAG) cascade, mitogen-activated protein (MAP) kinases, tyrosine kinases and RhoA/Rho kinase. Furthermore, Ang II elicits many of its (patho)physiological effects by stimulating reactive oxygen species (*O2- and H2O2) generation through activation of vascular NAD(P)H oxidase. *O2- and H2O2 in turn influence downstream signalling molecules including transcription factors, tyrosine kinases/phosphatases, Ca2+ channels and MAP kinases. Interaction between these systems is complex and dysregulation at any level may contribute to vascular remodelling. Targeting such molecules/pathways could prevent or induce regression of hypertensive vascular damage thereby ameliorating development of hypertension and preventing target organ damage. The present review discusses the role of Ang II in remodelling of resistance arteries, focusing on some signalling pathways involved in vascular growth and inflammation in hypertension.
 ...
PMID:Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. 1589 Jul 98


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