Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

Abstract

Background-Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo. Methods and Results-Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg · kg Ϫ1 · d Ϫ1 in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (PϽ0.05, nϭ15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both PϽ0.01, nϭ6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-␤ 2 , TGF-␤ 3 , and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both PϽ0.05, nϭ10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (PϽ0.05, nϭ5). Conclusions-These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure.

Rho kinase in the regulation of cell death and survival

“…The underlying mechanisms for the apoptotic role of ROCK in these studies are not defined, and effects of ROCK inhibitors in other cellular events such as inflammatory cell infiltration and cytokine production may be related to the anti-apoptotic effect of ROCK inhibitors. Consistent with the studies mentioned above, ROCK is involved in the regulation of inflammatory responses, such as production of inflammatory cytokines, inflammatory cell infiltration and vehicle secretions, in a number of experimental models [48,50,117,133], and these inflammatory responses may subsequently promote apoptosis. Finally, ROCK also regulates oxidative stress [49,125,150], which in turn can induce apoptosis.…”

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

“…PM 2.5 exposure increased cardiac RhoA activation, with reversal of these effects by fasudil, strongly indicating that RhoA/ROCK plays a significant role in mediating the effects of inhaled particulates on cardiac remodeling and BP. RhoA/ROCK has been demonstrated to be rapidly activated in response to various stimuli (3,18,23,44). Overexpression of constitutively active RhoA or dominant negative mutants in cardiomyocytes modulates the expression of various genes and pathways involved in cardiac hypertrophy (3,10,24), whereas ROCK inhibition attenuates cardiac hypertrophy in hypertensive strains and in response to exogenous ANG II (44,54).…”

“…Overexpression of constitutively active RhoA or dominant negative mutants in cardiomyocytes modulates the expression of various genes and pathways involved in cardiac hypertrophy (3,10,24), whereas ROCK inhibition attenuates cardiac hypertrophy in hypertensive strains and in response to exogenous ANG II (44,54). Recent studies (18,23,44,54) have also suggested an important role for RhoA/ROCK in myocardial fibrosis. A characteristic consequence of inhibition of ROCK is an amelioration of left ventricular fibrosis, as has been previously demonstrated in these studies.…”

Spectrum of Pleiotropic Effects of Statins in Heart Failure

“…[50] In animal infarct models, suppression of Rho kinase has been associated with attenuated LV remodeling. [51,52] Atorvastatin has been shown to reduce collagen synthesis, α-1-procollagen mRNA expression, and expression of the profibrotic peptide connective tissue growth factor in cell cultures of rat and human cardiac fibroblasts. [53] In a rat model of cardiac hypertrophy, treatment with pitavastatin led to a decrease in the expression of hypertrophic and profibrotic genes that was accompanied by significant decrease in interstitial fibrosis and collage deposition.…”