title: FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2.
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, cardiomyocyte-specific ROCK2-null (c-ROCK2(-/-)) were generated using conditional ROCK2(flox/flox) mice and α-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 cardiac-specific ROCK2-deficient mice.
authors.affiliation: Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02139, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okamoto
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.forename: Kensuke
authors.initials: K
authors.lastname: Noma
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hiroi
authors.forename: Ping-Yen
authors.initials: PY
authors.lastname: Liu
authors.forename: Masaya
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology; D054460:rho-Associated Kinases / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D000804:Angiotensin II; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases