ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice

Abstract

Pathological cardiac hypertrophy caused by diverse etiologies eventually leads to cardiac dilation and functional decompensation. We have recently reported that genetic deletion of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) inhibited several pathological events including cardiomyocyte apoptosis in compensated hypertrophic hearts. The present study investigated whether ROCK1 deficiency can prevent the transition from hypertrophy to heart failure. Transgenic mice with cardiac-restricted overexpression of Gαq develop compensated cardiac hypertrophy at young ages, but progress into lethal cardiomyopathy accompanied by increased apoptosis after pregnancy or at old ages. The studies were first carried out using age-and pregnancy-matched wildtype (WT), Gαq, ROCK1 −/− , and Gαq/ROCK1 −/− mice. The potent beneficial effect of ROCK1 deletion is demonstrated by abolishment of peripartum mortality, and significant attenuation of left ventricular (LV) dilation, wall thinning, and contractile dysfunction in the peripartum Gαq transgenic mice. Increase in cardiomyocyte apoptosis was suppressed by ROCK1 deletion, associated with increased extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation and inhibition of mitochondrial translocation of Bax. In addition, ROCK1 deficiency also improved survival, inhibited cardiomyocyte apoptosis, and preserved LV dimension and function in old Gαq mice at 12 months. Furthermore, transgenic overexpression of ROCK1 increased cardiomyocyte apoptosis and accelerated hypertrophic decompensation in Gαq hearts in the absence of pregnancy stress. The present study provides for the first time in vivo evidence for the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggests that ROCK1 may be an attractive therapeutic target to limit heart failure progression. KeywordsRho kinase; ROCK1; apoptosis; Gαq; ERK/MAPK; Bax; heart failure Heart failure is a leading cause for human morbidity and mortality, and the incidence of heart failure has been constantly increasing during the past decades. Cardiac hypertrophy is initially Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. a compensatory response to diverse etiologies, but it eventually leads to heart failure or sudden death due to decompensation [1][2][3]. Identifying the signaling mechanisms underlying the development of cardiac hypertrophy and the transition to heart failure will be helpful for the design of effective therapeutics. Rho-associated coiled-coil containing protein kinase (ROCK) is a downstream mediator o...

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

“…In contrast, although it does not prevent the development of cardiac hypertrophy, deletion of Rock1 improves survival, inhibits cardiomyocytes apoptosis, and preserves left ventricular structure and function in old G␣ q mice (442,443).…”

“…The resulting repression of the PI 3-kinase/Akt cell survival pathway thus sets on a positive feed-forward regulatory loop that favors cardiomyocyte apoptosis (72). Because cardiomyocyte apoptosis is a major cellular event involved in the transition from compensated hypertrophy to dilated cardiomyopathy and failure, this mechanism can support the observed important role of Rock1 in hypertrophic decompensation (443).…”

“…In a mouse model with cardiac specific overexpression of G␣ q , that develops compensated cardiac hypertrophy at young ages and progressing to heart failure, transgenic overexpression of Rock1 increases cardiomyocyte apopotosis and accelerates hypertrophic decompensation (443). In contrast, although it does not prevent the development of cardiac hypertrophy, deletion of Rock1 improves survival, inhibits cardiomyocytes apoptosis, and preserves left ventricular structure and function in old G␣ q mice (442,443).…”

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…Chronic treatment with ROCK inhibitors limits agonist-or myocardial infarction-induced pathologic cardiac remodeling and hypertrophy in mice, suggesting a role of ROCKs in these processes (Kobayashi et al, 2002;Higashi et al, 2003;Satoh et al, 2003;Hattori et al, 2004;Wang et al, 2005;Loirand et al, 2013). The cardioprotective effects of ROCK inhibitors have been attributed to a reduction of cardiomyocyte hypertrophy induced by increased mechanical strains or soluble hypertrophic signals (Hoshijima et al, 1998;Yanazume et al, 2002;Brown et al, 2006), limitation of fibrosis (Li et al, 2012a;Yang et al, 2012), and inhibition of cardiomyocyte apoptosis Shi et al, 2010) Although the mechanisms underlying the involvement of ROCK1 and/or ROCK2 and their respective roles in cardiac hypertrophy have not been completely elucidated, an increase in cardiac ROCK1 activity has been detected in response to pressure overload (Zhang et al, 2006). The subsequent effect of ROCK activation may be related to the stimulation of hypertrophic gene transcription (Kuwahara et al, 2010), downregulation of endothelial nitric oxide synthase (eNOS), and an increase in oxidative stress (Kobayashi et al, 2002;Mita et al, 2005).…”

Increased Rho kinase activity predicts worse cardiovascular outcome in ST-segment elevation myocardial infarction patients

“…Rho kinase 1 deletion did not impair compensatory hypertrophic response but significantly reduced cardiomyocyte apoptosis and fibrosis in response to pressure overload induced by transverse aortic constriction [24]. Another recent study showed the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggested that ROCK1 may be an attractive therapeutic target to limit heart failure progression [25]. In this study, the coronary angiography results showed that the coronary triple-vessel and left main lesion were more frequent in the DM group, but the Gensini score was similar between groups and the ROCK1 activity did not correlate with the Gensini score.…”