Communication Between Cardiomyocytes And Cardiac Fibroblasts: Mechanistic Role Of Rock1 In Fibrotic Cardiac Remodeling

Study objective Our previous study found that Rho associated coiled‐coil protein kinase 1 (ROCK1) was cleaved into an active isoform ROCKΔ1 in failing human hearts. The study is to investigate the pathological consequence of ROCKΔ1 accumulated in heart and the associated molecular mechanism. Methods and Results We generated transgenic mice expressing ROCKΔ1 in cardiomyocytes to mimic human heart disease. Mutant mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic heart displayed the activation of TGFβ1 and NF‐κB signaling. Treatment with Rho kinase inhibitor attenuated the phenotype. Cardiac fibroblasts were differentiated into myofibroblasts by co‐culturing with transgenic cardiomyocytes but not with wild‐type cardiomyocytes. Inhibitors of Rho kinase, TGFβR1 and NF‐κB diminished the process. A new cis ‐regulatory element of TGFβ1, the serum response factor‐dependent TGFβ1 regulation, was responsible for Rho kinase‐mediated TGFβ1 signaling activation. Conclusions The results demonstrate that ROCKΔ1 is a novel and potent fibrogenic factor. Activation of TGFβ1 and NF‐κB signaling along with a subset of cytokines released from cardiomyocytes induces cardiac fibroblast maturation, facilitates collagen deposition and macrophage infiltration. Both pathways synergistically contribute to Rho kinase‐mediated pathological fibrosis. Supported by NIH R01HL102314.