title: 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, 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 transgenic mice expressing ROCKΔ1 in cardiomyocytes to mimic the situation observed in human heart disease, whereas an additional kinase-deficient mouse was generated as a control. The ROCKΔ1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGFβ1 and NF-κB 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 TGFβR1 and NF-κB decreased these effects. The serum response factor-dependent TGFβ1 regulation was shown to be responsible for the Rho kinase-mediated activation of TGFβ1 signaling. We conclude that ROCKΔ1 is a novel fibrotic factor. Activation of TGFβ1 and NF-κB signaling contributes to the Rho kinase-mediated pathological fibrosis.
authors.affiliation: Texas A&M Health Science Center, Institute of Biosciences and Technology, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Ma
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.forename: Zhenyin
authors.initials: Z
authors.lastname: Tao
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Wallace L
authors.initials: WL
authors.lastname: Mckeehan
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000201:enzymology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005355:Fibrosis; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D017931:DNA Primers; D053773:Transforming Growth Factor beta1; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases