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Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging
Author(s) -
Shi Jianjian,
Surma Michelle,
Yang Yang,
Wei Lei
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802510r
Subject(s) - rock1 , rock2 , autophagy , pi3k/akt/mtor pathway , protein kinase b , rho associated protein kinase , microbiology and biotechnology , knockout mouse , kinase , myosin light chain kinase , cardiac fibrosis , focal adhesion , phosphorylation , fibrosis , biology , protein kinase a , cancer research , chemistry , signal transduction , medicine , apoptosis , biochemistry , receptor
In this study, we investigated the pathophysiological impact of Rho‐associated coiled‐coil–containing protein kinase (ROCK)1 and ROCK2 double deletion vs . single deletion on cardiac remodeling. Utilizing a cardiomyocyte‐specific and tamoxifen‐inducible MerCreMer recombinase (MCM), 3 mouse lines (MCM/ROCK1 f1/f1 / ROCK2 f1/f1 , MCM/ROCK1 f1/f1 , and MCM/ROCK2 f1/f1 ) were generated. As early as 5 d after inducible deletion, the double ROCK knockout hearts exhibited reduced phosphorylation of myosin light chain (MLC) and focal adhesion kinase (FAK), supporting a role for ROCK activity in regulating the nonsarcomeric cytoskeleton. Moreover, the autophagy marker microtubule‐associated proteins 1A‐1B light chain 3B was increased in the double ROCK knockout, and these early molecular features persisted throughout aging. Mechanistically, the double ROCK knockout promoted age‐associated or starvation‐induced autophagy concomitant with reduced protein kinase B (AKT), mammalian target of rapamycin (mTOR), Unc‐51‐like kinase signaling, and cardiac fibrosis. In contrast, ROCK2 knockout hearts showed increased phosphorylated (p)‐MLC and p‐FAK levels, which were mostly attributable to a compensatory ROCK1 overactivation. Autophagy was inhibited at the baseline accompanying increased mTOR activity, leading to increased cardiac fibrosis in the ROCK2 knockout hearts. Finally, the loss of ROCK1 had no significant effect on p‐MLC and p‐FAK levels, mTOR signaling, or autophagy at baseline. In summary, deletions of ROCK isoforms in cardiomyocytes have different, even opposite, effects on endogenous ROCK activity and the MLC/FAK/AKT/mTOR signaling pathway, which is involved in autophagy and fibrosis of the heart.—Shi, J., Surma, M., Yang, Y., Wei, L. Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging. FASEB J. 33, 7348–7362 (2019). www.fasebj.org