| First Author | Yang X | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 5 | Pages | 2105-16 |
| PubMed ID | 22278938 | Mgi Jnum | J:183286 |
| Mgi Id | MGI:5318169 | Doi | 10.1096/fj.11-201319 |
| Citation | Yang X, et al. (2012) Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1. FASEB J 26(5):2105-16 |
| abstractText | 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, ROCKDelta1. The purpose of the current investigation was to elucidate the pathological consequences of truncated ROCK1 accumulation in the heart, the associated molecular mechanism of ROCKDelta1-mediated cardiac phenotype, and the molecular signaling between Rho kinase activation in cardiomyocytes and extracellular matrix response. We generated transgenic mice expressing ROCKDelta1 in cardiomyocytes to mimic the situation observed in human heart disease, whereas an additional kinase-deficient mouse was generated as a control. The ROCKDelta1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGFbeta1 and NF-kappaB 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 TGFbetaR1 and NF-kappaB decreased these effects. The serum response factor-dependent TGFbeta1 regulation was shown to be responsible for the Rho kinase-mediated activation of TGFbeta1 signaling. We conclude that ROCKDelta1 is a novel fibrotic factor. Activation of TGFbeta1 and NF-kappaB signaling contributes to the Rho kinase-mediated pathological fibrosis.-Yang, X., Li, Q., Lin, X., Ma, Y., Yue, X., Tao, Z., Wang, F., Mckeehan, W. L., Wei, L., Schwartz, R. J., Chang, J. Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1. |
