Atorvastatin improves left ventricular remodeling and cardiac function in rats with congestive heart failure by inhibiting RhoA/Rho kinase‑mediated endothelial nitric oxide synthase

Abstract

The aim of the present study was to investigate the effects and possible mechanisms of atorvastatin (Ato) against chronic heart failure (CHF). A rat model of CHF was established and cardiac functions were assessed using Echocardiography. The expression of RhoA/Rho kinase and endothelial nitric oxide synthase (eNOS) was assessed using western blotting and reverse transcription polymerase chain reaction following 4 weeks of treatment. The three groups assessed in the present study were as follows: The control group (no treatment), the Ato + isopropylnoradrenaline (ISO) group (subcutaneous injections of 340 mg/kg ISO + orally administered 50 mg/kg Ato dissolved in saline; administered once daily) and the ISO group (subcutaneous injections of 340 mg/kg ISO + orally administered with an equal volume of saline; administered once daily). Heart volume and weight in the ISO group were significantly increased compared with the control (C) group (P<0.01), whereas contractility was decreased. The results were reverse for the Ato group when compared with the ISO group (P<0.05). Levels of RhoA/Rho kinase protein and mRNA were significantly increased in the ISO group (P<0.01); however. The mRNA and protein expression of eNOS was significantly decreased (P<0.05) when compared with the C group. The mRNA and protein expression of RhoA/Rho kinase was significantly reduced in the Ato+ISO group compared with the ISO group (P<0.01), whereas the mRNA and protein expression of eNOS was significantly increased (P<0.05). RhoA protein expression was increased in the cytoplasm of the C group and on the cell membrane of the ISO group; however, in the Ato+ISO group, RhoA protein expression on the cell membrane was significantly downregulated when compared with the ISO group (P<0.05). The results of the present study suggest that Ato upregulates eNOS by inhibiting RhoA/Rho kinase overexpression in the myocardial tissue of rats with CHF, thus improving left ventricular remodeling and cardiac function.

Inhibition of�Rho‑kinase is involved in the therapeutic effects of atorvastatin in heart ischemia/reperfusion

“…It has also been revealed that atorvastatin prevents pulmonary vascular remodeling by inhibiting RhoA/Rho-kinase (40). Moreover, atorvastatin may upregulate NO levels via Rho-kinase signaling (41). Similar to our previous studies showing that the activation of Rho-kinase can be significantly upregulated by heart I/R injury (13,42), the present results suggested that myocardial I/R caused a significant increase in Rho-kinase activity.…”

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

“…These effects are mediated by NO production [63]. Atorvastatin blocks the RhoA/Rho kinase pathway and increases the amount of mRNA for eNOS [64]. Upregulation of eNOS expression by statins increases capillary density and/or improves endothelial function, leading to better myocardial perfusion and improvement of HF [65].…”

Using Omics to Identify Novel Therapeutic Targets in Heart Failure

“…114 Atorvastatin decreased Rac1 protein expression and improved cardiac function in an animal model. 115 However, clinical trials of statins have not yet confirmed these findings, and debate remains on the clinical utility of statin therapy in HF. 116,117 Additionally, a RAC1 inhibitor, NSC23766, has shown a reduction in cardiac remodeling and cellular hypertrophy in animal and cellular studies, demonstrating RAC1 as a potential druggable target.…”