Rosuvastatin Provides Pleiotropic Protection Against Pulmonary Hypertension, Right Ventricular Hypertrophy and Coronary Endothelial Dysfunction in Rats

Abstract

Recent human and animal studies reported the pleiotropic effects of HMG-CoA reductase inhibitors (Statins) independent of their actions on blood lipids, suggesting they may represent novel mechanisms for the treatment of multiple organ damages in cardiovascular diseases. The present study is aimed to investigate if oral rosuvastatin (RS, 2mg/kg/day) treatment could prevent the monocrotaline (MCT) -induced pulmonary hypertension (PH), as well as provide protection against right ventricular hypertrophy (RVH) and coronary endothelial (CEC) dysfunction associated with PH. One month after a single MCT injection (60mg/kg), rats developed severe PH and RVH. CEC function, assessed with the endothelium/NO-dependent response to acetylcholine and L-NAME, also showed a significant attenuation in right, but not left, coronary arteries. RS treatment, one week before MCT (early therapy), prevented the development of PH, RVH and CEC dysfunction. Exaggerated vasoconstriction to U46619, a thromboxane analogue, in MCT control rats was also inhibited in the RS-treated group. Sodium nitroprusside, a direct NO donor, induced EC-independent coronary dilation was not affected either by MCT or RS administration. RS treatment, one week after MCT (late therapy), also induced a protection against RVH and CEC dysfunction, but did not prevent the development of PH. Further study of RS treatment in normal rats confirmed the beneficial effect of RS on coronary EC function. Taken together, these findings demonstrate, for the first time, the pleiotropic effects of rosuvastatin against PH, RVH and CEC dysfunction in rats. The cardiac protection is probably mediated via statin preservation of coronary endothelial function. (Supported by NIH NCCAM RO1 AT-001235)