FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2

Ryuji Okamoto, Yuxin Li, Kensuke Noma, Yukio Hiroi, Ping Yen Liu, Masaya Taniguchi, Masaaki Ito, James K. Liao

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Abstract

The Rho-associated coiled-coil containing kinases, ROCK1 and ROCK2, are important regulators of cell shape, migration, and proliferation through effects on the actin cytoskeleton. However, it is not known whether ROCK2 plays an important role in the development of cardiac hypertrophy. To determine whether the loss of ROCK2 could prevent cardiac hypertrophy, cardiomyocytespecific ROCK2-null (c-ROCK2-/-) were generated using conditional ROCK2 flox/flox mice and myosin heavy-chain promoter-driven Cre recombinase transgenic mice. Cardiac hypertrophy was induced by Ang II infusion (400 ng/kg/ min, 28 d) or transverse aortic constriction (TAC). Under basal conditions, hemodynamic parameters, cardiac anatomy, and function of c-ROCK2-/- mice were comparable to wild-type (WT) mice. However, following Ang II infusion or TAC, c-ROCK2-/- mice exhibited a substantially smaller increase in heart-to-body weight ratio, left ventricular mass, myocyte cross-sectional area, hypertrophy-related fetal gene expression, intraventricular fibrosis, cardiac apoptosis, and oxidative stress compared to control mice. Deletion of ROCK2 in cardiomyocytes leads to increased expression of four-and-a-half LIM-only protein-2 (FHL2) and FHL2- mediated inhibition of serum response factor (SRF) and extracellular signal-regulated mitogen-activated protein kinase (ERK). Knockdown of FHL2 expression in ROCK2-deficient cardiomyocytes or placing ROCK2-haploinsufficient (ROCK2+/-) mice on FHL2 +/-- haploinsufficient background restored the hypertrophic response to Ang II. These results indicate that cardiomyocyte ROCK2 is essential for the development of cardiac hypertrophy and that up-regulation of FHL2 may contribute to the antihypertrophic phenotype that is observed in cardiacspecific ROCK2-deficient mice.-Okamoto, R., Li, Y., Noma, K., Hiroi, Y., Liu, P.-Y., Taniguchi, M., Ito, M., Liao, J. K. FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. FASEB J. 27, 1439-1449 (2013). www.fasebj.org.

Original languageEnglish
Pages (from-to)1439-1449
Number of pages11
JournalFASEB Journal
Volume27
Issue number4
DOIs
Publication statusPublished - 2013 Apr 1

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Okamoto, R., Li, Y., Noma, K., Hiroi, Y., Liu, P. Y., Taniguchi, M., Ito, M., & Liao, J. K. (2013). FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. FASEB Journal, 27(4), 1439-1449. https://doi.org/10.1096/fj.12-217018