Submitted on September 17, 2007
Accepted on January 30, 2008
Effects of a rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction
Arintaya Phrommintikul1, Lavinia Tran2, Andrew Kompa3, Bing Wang4, Anastasia Adhrahtas2, Danielle Cantwell2, and Henry Krum4*
1 Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Internal Medicine, Chiang Mai University, Thailand
2 Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
3 Medicine, Monash University, Melbourne, Tasmania, Australia; Medicine, University of Melbourne, Melbourne, Victoria, Australia
4 Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Medicine, Monash University, Melbourne, Tasmania, Australia
* To whom correspondence should be addressed. E-mail: henry.krum{at}med.monash.edu.au.
The RhoA-Rho kinase (ROCK) signalling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure-overload induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into 4 groups: GSK576371 1 (GSK1, n=9) or 3mg/kg bid (GSK3, n=10), ramipril 1mg/kg/day (n=10) or vehicle (n=11) treatment for 4 weeks. Sham animals (n=11) underwent surgery without banding. Echocardiograms were performed before surgery and post-treatment, haemodynamic data was obtained at completion of the study. Echocardiography showed an increase in relative wall thickness (RWT) of the left ventricle (LV) following POH+Vehicle treatment compared to sham animals. This was attenuated by both doses of GSK576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time and MV annular velocity which were dose-dependently restored toward sham values by GSK576371. LV end diastolic pressure was increased following POH+Vehicle treatment compared to sham (6.9±0.7 vs. 3.2±0.7 mmHg, p=0.008), and was reduced with GSK3 and ramipril treatment (1.7±0.7, p<0.01 and 2.9±0.6 mmHg, p<0.01 respectively). Collagen I deposition in the LV was increased following POH+Vehicle treatment (32.2%; p<0.01) compared to sham animals and significantly attenuated with GSK1 (21.7%; p<0.05), GSK3 (23.8%; p<0.01) and ramipril (35.5%; p<0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.
