ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice.
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 wild-type, 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.
Shi
Jianjian
J
Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University, School of Medicine, Indianapolis, IN 46202-5225, USA.
Zhang
Yi-Wei
YW
Yang
Yu
Y
Zhang
Lumin
L
Wei
Lei
L
D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D017353:Gene Deletion; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006334:Heart Function Tests; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11