Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aging is a major risk factor for the development of vascular diseases that lead to stroke and heart failure. Several cellular factors such as cell adhesion, motility, contractile response, and cytokinesis are involved in the aging process. RhoA, a member of the Rho family, plays a primary role in the regulation of these cellular factors. This study aims to investigate whether RhoA is involved in these age-related responses to vascular change. We found that in older rats (19 months ole), RhoA mRNA increased 1.9-fold in the aortic arteries and 2.4-fold in the basilar arteries compared to the younger rats (2 months old). Membrane binding, but not cytosol RhoA, levels were found to significantly increase in the aortic and basilar arteries with age, which suggests that RhoA activity increases in older rats. Staining of RhoA increased markedly with age in both the medial and endothelial layers of the collected aortic and basilar arteries. These results show that RhoA expression and activity in the aortic and basilar arteries increased as a function of age, thereby suggesting that RhoA might be altered in the vascular response change of aged rats.
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PMID:Age-related RhoA expression in blood vessels of rats. 1155 78

Two mechanisms are proposed to account for the inhibition of myosin phosphatase (MP) involved in Ca2+ sensitization of vascular muscle, ie, phosphorylation of either MYPT1, a target subunit of MP or CPI-17, an inhibitory phosphoprotein. In cultured vascular aorta smooth muscle cells (VSMCs), stimulation with angiotensin II activated RhoA, and this was blocked by pretreatment with 8-bromo-cGMP. VSMCs stimulated by angiotensin II, endothelin-1, or U-46619 significantly increased the phosphorylation levels of both MYPT1 (at Thr696) and CPI-17 (at Thr38). The angiotensin II-induced phosphorylation of MYPT1 was completely blocked by 8-bromo-cGMP or Y-27632 (a Rho-kinase inhibitor), but not by GF109203X (a PKC inhibitor). In contrast, phosphorylation of CPI-17 was inhibited only by GF109203X. Y-27632 dramatically corrected the hypertension in N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated rats, and this hypertension also was sensitive to isosorbide mononitrate. The level of the active form of RhoA was significantly higher in aortas from L-NAME-treated rats. Expression of RhoA, Rho-kinase, MYPT1, CPI-17, and myosin light chain kinase were not significantly different in aortas from L-NAME-treated and control rats. Activation of RhoA without changes in levels of other signaling molecules were observed in three other rat models of hypertension, ie, stroke-prone spontaneously hypertensive rats, renal hypertensive rats, and DOCA-salt rats. These results suggest that independent of the cause of hypertension, a common point in downstream signaling and a critical component of hypertension is activation of RhoA and subsequent activation of Rho-kinase.
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PMID:Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. 1260 Aug 88

Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.
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PMID:G13 is an essential mediator of platelet activation in hemostasis and thrombosis. 1452 98

RhoA is commonly activated in the aorta in various hypertensive models, indicating that RhoA seems to be a molecular switch in hypertension. The molecular mechanisms for RhoA activation in stroke-prone spontaneously hypertensive rats (SHRSP) were here investigated using cultured aortic smooth muscle cells (VSMC). The level of the active form of RhoA was higher in VSMC from SHRSP than in those from Wistar-Kyoto rats (WKY). The phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) at the inhibitory site was also significantly higher in SHRSP, and the phosphorylation levels in both VSMCs were strongly inhibited to a similar extent by treatment with Y-27632, a Rho-kinase inhibitor. The expression levels of RhoA/Rho-kinase related molecules, namely RhoA, Rho-kinase, MYPT1, CPI-17 (inhibitory phosphoprotein for myosin phosphatase) and myosin light chain kinase, were not different between SHRSP and WKY. Valsartan, an angiotensin II (Ang II)- type 1 receptor antagonist, selectively and significantly reduced the RhoA activation in VSMC from SHRSP. The expression levels of the Rho GDP-dissociation inhibitor (RhoGDI) and leukemia-associated Rho-specific guanine nucleotide exchange factor (RhoGEF) did not differ between SHRSP and WKY. In cyclic nucleotide signaling, cyclic GMP (cGMP)-dependent protein kinase Ialpha (cGKIalpha) was significantly downregulated in SHRSP cells, although there were no changes in the expression levels of guanylate cyclase beta and cyclic AMP (cAMP)-dependent protein kinase or the intracellular contents of cGMP and cAMP between the two rat models. These results suggest that the possible mechanisms underlying RhoA activation in VSMC from SHRSP are autocrine/paracrine regulation by Ang II and/or cGKIalpha downregulation.
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PMID:RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. 1512 84

Hypertension is risk factor for cardiovascular morbidity and mortality, and stroke. A critical surge in blood pressure occurs during the early morning hours coincident with increased incidences of myocardial infarction, unstable angina, stroke and sudden cardiac death. This suggests that, in patients with hypertension, it may be important to maintain the efficacy of antihypertensive medication over the 24-h dosing interval, especially in the risky early morning hours. In order to evaluate the antihypertensive efficacies of fixed-dose combinations of angiotensin II receptor blockers with hydrochlorothiazide (HCTZ) 12.5 mg, a multicenter, randomized, prospective, open-label, blinded-endpoint study was performed in 805 patients with mild-to-moderate hypertension randomized to once-daily treatment with telmisartan 40 mg plus HCTZ (T40/H12.5), losartan 50 mg plus HCTZ (L50/H12.5), or telmisartan 80 mg plus HCTZ (T80/H12.5), with the primary objective of comparing T40/H12.5 with L50/H12.5 and evaluating the additional response of T80/H12.5. Efficacy was assessed by ambulatory blood pressure monitoring (ABPM), clinic seated cuff sphygmomanometry and calculated responder rates after 6 weeks' active treatment. The primary endpoint was reduction from baseline in the last 6-h mean (relative to dosing) diastolic blood pressure (DBP) measured using 24-h ABPM. Compared with the L50/H12.5 group, the mean reductions in the last 6-h mean DBP for the T40/H12.5 and T80/H12.5 groups were significantly greater: -2.0 mmHg (p=0.0031) and -2.8 mmHg (p=0.0003), respectively. We conclude that T40/H12.5 provided clinically and statistically significantly superior blood pressure reductions compared with L50/H12.5 during the last 6 h of the 24-h dosing interval, which corresponds to the high-risk early-morning hours, and that T80/H12.5 provided additional blood pressure reductions.
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PMID:Telmisartan/Hydrochlorothiazide in comparison with losartan/hydrochlorothiazide in managing patients with mild-to-moderate hypertension. 1633 83

Rho-associated kinases (ROCKs), the immediate downstream targets of RhoA, are ubiquitously expressed serine-threonine protein kinases that are involved in diverse cellular functions, including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility, and gene expression. Recent studies have shown that ROCKs may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, and heart failure. Indeed, inhibition of ROCKs by statins or other selective inhibitors leads to the upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. Thus inhibition of ROCKs may contribute to some of the cholesterol-independent beneficial effects of statin therapy. Currently, two ROCK isoforms have been identified, ROCK1 and ROCK2. Because ROCK inhibitors are nonselective with respect to ROCK1 and ROCK2 and also, in some cases, may be nonspecific with respect to other ROCK-related kinases such as myristolated alanine-rich C kinase substrate (MARCKS), protein kinase A, and protein kinase C, the precise role of ROCKs in cardiovascular disease remains unknown. However, with the recent development of ROCK1- and ROCK2-knockout mice, further dissection of ROCK signaling pathways is now possible. Herein we review what is known about the physiological role of ROCKs in the cardiovascular system and speculate about how inhibition of ROCKs could provide cardiovascular benefits.
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PMID:Physiological role of ROCKs in the cardiovascular system. 1646 61

Axons fail to regenerate in the adult central nervous system (CNS) following injury. Developing strategies to promote axonal regeneration is therapeutically attractive for various CNS pathologies such as traumatic brain injury, stroke and Alzheimer's disease. Because the RhoA pathway is involved in neurite outgrowth, Rho-associated kinases (ROCKs), downstream effectors of GTP-bound Rho, are potentially important targets for axonal repair strategies in CNS injuries. We investigated the effects and downstream mechanisms of ROCK inhibition in promoting neurite outgrowth in a PC-12 cell model. Robust neurite outgrowth (NOG) was induced by ROCK inhibitors Y-27632 and H-1152 in a time-and dose-dependent manner. Dramatic cytoskeletal reorganization was noticed upon ROCK inhibition. NOG initiated within 5 to 30 minutes followed by neurite extension between 6 and 10 hours. Neurite processes were then sustained for over 24 hours. Rapid cofilin dephosphorylation was observed within 5 minutes of Y-27632 and H-1152 treatment. Re-phosphorylation was observed by 6 hours after Y-27632 treatment, while H-1152 treatment produced sustained cofilin dephosphorylation for over 24 hours. The results suggest that ROCK-mediated dephosphorylation of cofilin plays a role in the initiation of NOG in PC-12 cells.
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PMID:Direct Rho-associated kinase inhibition [correction of inhibiton] induces cofilin dephosphorylation and neurite outgrowth in PC-12 cells. 1684 45

1. In the present study, we investigated the effects of chronic treatment of stroke-prone spontaneously hypertensive rats (SHRSP) with the statin fluvastatin on vascular Rho/Rho-kinase pathway mediated contraction, which has been shown to be upregulated in hypertension. 2. Contribution of the Rho/Rho-kinase pathway to noradrenaline-induced contraction of arteries from SHRSP was assessed by the inhibitory effect of Y-27632, a Rho/Rho-kinase inhibitor. Stroke-prone spontaneously hypertensive rats were treated with fluvastatin (10 mg/kg per day) for 1 month. 3. Treatment with fluvastatin tended to attenuate the contraction to noradrenaline and significantly decreased the Y-27632-sensitive component of the contraction in controls compared with fluvastatin-treated rats. 4. RhoA, as assessed by western blotting, was also reduced by fluvastatin treatment. 5. These findings suggest that chronic treatment with fluvastatin reduces the contractile response associated with Rho/Rho-kinase in arteries of hypertensive rats.
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PMID:Chronic fluvastatin treatment alters vascular contraction by inhibiting the Rho/Rho-kinase pathway. 1689 38

We have investigated the gene expression in human middle cerebral artery (MCA) after ischemia. Ischemic stroke affects the perfusion in the affected area and experimental cerebral ischemia results in upregulation of vasopressor receptors in the MCA leading to the ischemic area. We obtained human MCA samples distributing to the ischemic area, 7-10 days post-stroke. The gene expression was examined with real-time polymerase chain reaction (PCR) and microarray, proteins were studied with immunohistochemistry. We investigated genes previously shown to be upregulated in animal models of cerebral ischemia (e.g. ET(A), ET(B), AT1, AT2, and 5-HT(2A/1B/1D)). Their mRNA expression was increased compared with controls, consistent with findings in experimental stroke. Immunohistochemistry showed upregulation of the receptors localized on the smooth muscle cells. The gene expression was profiled with microarray and seven genes chosen for further investigation with real-time PCR; ELK3, LY64, Metallothionin IG, POU3F4, Actin alpha2, RhoA and smoothelin. Six of these were regulated the same way when confirming array expression with real-time PCR. Gene expression studies in the human MCA leading to the ischemic region is similar to that seen after MCA occlusion in rats. We found new genes that support the dynamic changes that occur in the MCA distributing to the ischemic region.
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PMID:Gene expression profiling in the human middle cerebral artery after cerebral ischemia. 1711 15

Functional recovery following acute CNS injury in humans, such as spinal cord injury and stroke, is exceptionally limited, leaving the affected individual with life-long neurological deficits such as loss of limb movement and sensation leading to a compromised quality of life. As yet, there is no effective treatment on the market for such injuries. This lack of functional recovery can at least in part be attributed to the restriction of axonal regeneration and neuroplasticity by several CNS myelin proteins that have been shown to be potent inhibitors of neurite outgrowth in vitro, namely myelin-associated glycoprotein (MAG), Nogo-A and oligodendrocyte myelin glycoprotein (OMgp). Nogo-A contains multiple neurite outgrowth inhibitory domains exposed on the surface of myelinating oligodendrocytes located within its amino-terminal region (amino-Nogo-A) and C-terminal region (Nogo-66). Although structurally dissimilar; Nogo-66, MAG and OMgp exert their inhibitory effects by binding the GPI-linked neuronal Nogo-66 receptor (NgR) that transduces the inhibitory signal to the cell interior via transmembrane co-receptors LINGO-1 and p75(NTR)or TROY. Although the receptor(s) for amino-Nogo-A are unknown, amino-Nogo-A and NgR ligands mutually activate the small GTPase RhoA. Consistent with their neurite outgrowth inhibitory function, approaches counter-acting Nogo-A using function-blocking antibodies, NgR using peptide antagonists and receptor bodies or RhoA using deactivating enzymes have been shown to significantly enhance axonal regeneration and neuroplasticity leading to improved functional recovery in animal models of acute CNS injury. These in vivo findings thus provide a sound basis for the development of an effective treatment for acute CNS injuries in humans.
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PMID:Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. 1769 15


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