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GW24-e1389 Rho Signalling and Cardiomyopathy
  1. Jiang Chang,
  2. Xiangsheng Yang
  1. Institute of Biosciences and Technology, Texas A&M University Health Science Center

Abstract

Objectives Rho associated coiled-coil protein kinase 1 (ROCK1) activity has been shown to closely associate with various cardiovascular diseases.

Methods To define the pathological consequence of this constitutively activated ROCK∆1 accumulated in human failing myocardium in vivo, we generated transgenic mice expressing ROCK∆1 in cardiomyocytes to mimic the situation observed in human heart disease. Several genetic mouse models along with cell culture experiments were applied in this study.

Results The ROCK∆1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGFb1 and NF-κB signalling 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.

We elucidated the molecular mechanism underlying ROCK∆1-mediated fibrotic cardiomyopathy, and demonstrated that TGFβ1 was a new target gene of SRF (serum response factor). ROCK∆1 activated SRF through manipulating actin dynamic changes, which then facilitated TGFβ1 transcriptional expression. The SRF-mediated TGFβ1 transcriptional regulation was further demonstrated by genetic deletion of SRF specifically in mouse heart, which led to marked decrease in TGFβ1 expression.

Conclusions This study demonstrated the pro-fibrotic role of truncated ROCK1 in vivo and provided an animal model to recapitulate human heart failure. Activation of TGFβ1 and NF-κB signalling along with a subset of cytokines released from cardiomyocytes induced cardiac fibroblast maturation, facilitated collagen deposition and macrophage infiltration. Both pathways synergistically contributed to Rho kinase-mediated pathological fibrosis. The study provided a new therapeutic and mechanistic insight into Rho kinase inhibitor treatment in heart failure.

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