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Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1.


ABSTRACT: We have previously found that in failing human hearts, Rho-associated coiled-coil protein kinase 1 (ROCK1) is processed by caspase-3 into an active isoform, ROCK?1. The purpose of the current investigation was to elucidate the pathological consequences of truncated ROCK1 accumulation in the heart, the associated molecular mechanism of ROCK?1-mediated cardiac phenotype, and the molecular signaling between Rho kinase activation in cardiomyocytes and extracellular matrix response. We generated transgenic mice expressing ROCK?1 in cardiomyocytes to mimic the situation observed in human heart disease, whereas an additional kinase-deficient mouse was generated as a control. The ROCK?1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGF?1 and NF-?B signaling and a release of a subset of cytokines and were susceptible to angiotensin II stress. Treatment with a Rho kinase inhibitor attenuated the fibrotic phenotype. Cardiac fibroblasts differentiated into myofibroblasts when cocultured with transgenic cardiomyocytes but not with wild-type cardiomyocytes. Inhibitors of Rho kinase as well as TGF?R1 and NF-?B decreased these effects. The serum response factor-dependent TGF?1 regulation was shown to be responsible for the Rho kinase-mediated activation of TGF?1 signaling. We conclude that ROCK?1 is a novel fibrotic factor. Activation of TGF?1 and NF-?B signaling contributes to the Rho kinase-mediated pathological fibrosis.

SUBMITTER: Yang X 

PROVIDER: S-EPMC3336781 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1.

Yang Xiangsheng X   Li Qi Q   Lin Xi X   Ma Yanlin Y   Yue Xiaojing X   Tao Zhenyin Z   Wang Fen F   Mckeehan Wallace L WL   Wei Lei L   Schwartz Robert J RJ   Chang Jiang J  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120125 5


We have previously found that in failing human hearts, Rho-associated coiled-coil protein kinase 1 (ROCK1) is processed by caspase-3 into an active isoform, ROCKΔ1. The purpose of the current investigation was to elucidate the pathological consequences of truncated ROCK1 accumulation in the heart, the associated molecular mechanism of ROCKΔ1-mediated cardiac phenotype, and the molecular signaling between Rho kinase activation in cardiomyocytes and extracellular matrix response. We generated tran  ...[more]

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