Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular mechanical and contractile properties were compared in adult (6 months old) and very-aged (36 months old) Fischer 344/NNiaHSd X Brown Norway/BiNia (F344/NXBN) rats. Our previous work has indicated that aging is associated with aortic medial thickening. This morphological alteration was accompanied by a leftward shift in the aortic stress/strain curve indicating increased vessel stiffness in very-aged animals. Disruption of the endothelium as well as pretreatment of tissues with the nitric oxide (NO) donor sodium nitroprusside eliminated differences, suggesting a link between deficient endothelial NO release and reduced compliance in very-aged aortae. In addition, the Rho kinase inhibitor Y-27632 increased vessel compliance in both adult and very-aged tissues suggesting that the Rho cascade contributed to the stress/strain relationship. Maximal force developed in response to high potassium (K(+)) was reduced by approximately 70% in intact and endothelium-denuded aortae from very-aged rats. In contrast to contractile force development, calcium-dependent stress relaxation was increased in very-aged aorta. Finally, gel electrophoresis indicated a significantly higher tissue content of myosin heavy chain and a higher ratio of SM1/SM2 isoforms with aging. The results suggest multiple molecular changes with aging, which may be expected to alter vascular tissue function.
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PMID:Aging alters mechanical and contractile properties of the Fisher 344/Nnia X Norway/Binia rat aorta. 1716 81

The small G-protein RhoA regulates the actin cytoskeleton, and its involvement in cell proliferation has also been established. In contrast, little is known about whether RhoA participates in cell survival or apoptosis. In cardiomyocytes in vitro, RhoA induces hypertrophic cell growth and gene expression. In vivo, however, RhoA expression leads to development of heart failure (Sah, V. P., Minamisawa, S., Tam, S. P., Wu, T. H., Dorn, G. W., Ross, J. Jr., Chien, K. R., and Brown, J. H. (1999) J. Clin. Investig. 103, 1627-1634), a condition widely associated with cardiomyocyte apoptosis. We demonstrate here that adenoviral overexpression of activated RhoA in cardiomyocytes induces hypertrophy, which transitions over time to apoptosis, as evidenced by caspase activation and nucleosomal DNA fragmentation. The Rho kinase inhibitors Y-27632 and HA-1077 and expression of a dominant negative Rho kinase block these responses. Caspase-9, but not caspase-8, is activated, and its inhibition prevents DNA fragmentation, consistent with involvement of a mitochondrial death pathway. Interestingly, RhoA expression induces a 3-4-fold up-regulation of the proapoptotic Bcl-2 family protein Bax. RhoA also increases levels of activated Bax and the amount of Bax protein localized at mitochondria. Bax mRNA is increased by RhoA, indicating transcriptional regulation, and the ability of a dominant negative p53 mutant to block Bax up-regulation implicates p53 in this response. The involvement of Bax in RhoA-induced apoptosis was examined by treatment with a Bax-inhibitory peptide, which was found to significantly attenuate DNA fragmentation and caspase-9 and -3 activation. The dominant negative p53 also prevents RhoA-induced apoptosis. We conclude that RhoA/Rho kinase activation up-regulates Bax through p53 to induce a mitochondrial death pathway and cardiomyocyte apoptosis.
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PMID:RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. 1723 27

The RhoA/Rho kinase (ROCK) pathway is a new mechanism of remodeling and vasoconstriction. Few data are available regarding ROCK activation when angiotensin I-converting enzyme is high and blood pressure is normal. We hypothesized that ROCK is activated in the vascular wall in normotensive rats with genetically high angiotensin I-converting enzyme levels, and it causes increased vascular expression of genes promoting vascular remodeling and also oxidative stress. Aortic ROCK activation, mRNA and protein levels (of monocyte chemoattractant protein-1, transforming growth factor [TGF]-beta(1), and plasminogen activator inhibitor-1 [PAI-1]), NADPH oxidase activity, and O(2)(*-) production were measured in normotensive rats with genetically high (Brown Norway [BN]) and low (Lewis) angiotensin-I-converting enzyme levels and in BN rats treated with the ROCK antagonist fasudil (100 mg/kg per day) for 7 days. ROCK activation was 12-fold higher in BN versus Lewis rats (P<0.05) and was reduced with fasudil by 100% (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 mRNA levels were higher in BN versus Lewis rats by 300%, 180%, and 1000%, respectively (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein levels were higher in BN versus Lewis rats (P<0,05). Fasudil reduced TGF-beta1 and PAI-1 mRNA and TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein aortic levels to those observed in Lewis rats. Aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and (*)O(2)(-) production were increased by 88% and 300%, respectively, in BN rats (P<0.05) and normalized by fasudil. In conclusion, ROCK is significantly activated in the aortic wall in normotensive rats with genetically high angiotensin-I-converting enzyme and angiotensin II, and it causes activation of genes that promote vascular remodeling and also increases vascular oxidative stress.
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PMID:Rho kinase activation and gene expression related to vascular remodeling in normotensive rats with high angiotensin I converting enzyme levels. 1778 32

RhoA a small G-protein that has an established role in cell growth and in regulation of the actin cytoskeleton. Far less is known about whether RhoA can modulate cell fate. We previously reported that sustained RhoA activation induces cardiomyocyte apoptosis (Del Re, D. P., Miyamoto, S., and Brown, J. H. (2007) J. Biol. Chem. 282, 8069-8078). Here we demonstrate that less chronic RhoA activation affords a survival advantage, protecting cardiomyocytes from apoptotic insult induced by either hydrogen peroxide treatment or glucose deprivation. Under conditions where RhoA is protective, we observe Rho kinase-dependent cytoskeletal rearrangement and activation of focal adhesion kinase (FAK). Activation of endogenous cardiomyocyte FAK leads to its increased association with the p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and to concomitant activation of Akt. Treatment of isolated perfused hearts with sphingosine 1-phosphate recapitulates this response. The pathway by which RhoA mediates cardiomyocyte Akt activation is demonstrated to require Rho kinase, FAK and PI3K, but not Src, based on studies with pharmacological inhibitors (Y-27632, LY294002, PF271 and PP2) and inhibitory protein expression (FAK-related nonkinase). Inhibition of RhoA-mediated Akt activation at any of these steps, including inhibition of FAK, prevents RhoA from protecting cardiomyocytes against apoptotic insult. We further demonstrate that stretch of cardiomyocytes, which activates endogenous RhoA, induces the aforementioned signaling pathway, providing a physiologic context in which RhoA-mediated FAK phosphorylation can activate PI3K and Akt. We suggest that RhoA-mediated effects on the cardiomyocyte cytoskeleton provide a novel mechanism for protection from apoptosis.
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PMID:Focal adhesion kinase as a RhoA-activable signaling scaffold mediating Akt activation and cardiomyocyte protection. 1885 12