Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats

Abstract

We recently reported that increased vascular endothelial nitric oxide production could protect against the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH) in rats (32). The present study investigated whether the pleiotropic action of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in upregulating endothelial function could also protect against the MCT-induced end-organ damages. Rosuvastatin (2 mg kg(-1) day(-1) via oral gavage) or placebo was initiated 1 wk before or 1 wk after MCT (60 mg/kg ip) administration. One month after MCT, significant PAH developed in the placebo rats, which were accompanied by histological evidence of pulmonary vascular thickening and right ventricular hypertrophy. The coronary endothelial vasodilatory function, assessed with endothelial/nitric oxide-dependent responses to acetylcholine and N(G)-nitro-L-arginine methyl ester (L-NAME), was depressed, while the constrictory responses to known coronary constrictors was enhanced. In rats that received rosuvastatin treatment 1 wk before MCT administration, a significantly reduced PAH and RVH was observed, as well as reduced pulmonary vascular and right ventricular remodelings. Rosuvastatin 1-wk posttreatment had no effect on PAH, but inhibited RVH. Right coronary endothelial dysfunction, which was shown in placebo rats, was effectively prevented by both pre- and postrosuvastatin treatment, while this effect was more dramatic in the pretreated group. Left coronary endothelial function, which was not affected by MCT, also showed an upregulation by rosuvastatin. Taken together, our results demonstrated the pleiotropic protection of rosuvastatin against the development of PAH and RVH and confirmed our previous finding that the targeted preservation of coronary endothelial function and vasoactivity may provide a novel approach to protect against cardiac remodeling.

Simvastatin as a Treatment for Pulmonary Hypertension Trial

“…Evidence of potential therapeutic benefit from this drug class comes from a series of animal studies but there are no robust data from studies in patients (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Because the response of the RV to the increased afterload in PAH is an important determinant of patient outcome (18)(19)(20)(21), this study examined prospectively the effect of simvastatin on RV mass and function in patients with PAH.…”

“…This spectrum of activity arises from the inhibition of isoprenoids (geranylgeranylpyrophosphate and farnesylpyrophosphate), which are essential for the post-translational isoprenylation of Rho and Ras family GTPases. Statins, in particular simvastatin, have been reported to attenuate the development of pulmonary hypertension in a number of experimental animal models (4)(5)(6)(7)(8)(9)(10)(11)(12) and to regress established pulmonary hypertension and vascular remodeling induced by either pneumonectomy and monocrotaline treatment (13) or chronic hypoxia (14). There is evidence that this is achieved through increased apoptosis as well as reduced proliferation of smooth muscle cells in obstructive vascular lesions.…”

“…There is evidence that this is achieved through increased apoptosis as well as reduced proliferation of smooth muscle cells in obstructive vascular lesions. Of interest, not all studies report a reduction in pulmonary artery pressure (12,15,16), but a reduction in right ventricular (RV) hypertrophy appears to be a consistent finding (4)(5)(6)(7)(8)(9)(12)(13)(14)(15)(16).…”

Rosuvastatin, Sildenafil and Their Combination in Monocrotaline-Induced Pulmonary Hypertension in Rat

“…Satoh et al (7) did not observe 28-d pravastatin administration to have any significant impact on the reduction of elevated right ventricular pressure (RVP) and cardiac hypertrophy in a mono-crotaline (MCT) rat model. In opposite, Sun et al (8) showed that another hydrophilic statin -rosuvastatin when given especially for early protection against PH development had positive impact on myocardial hypertrophy and reduction of pulmonary pressure. Also, the benefits of adding statins to a conventional regimen have been investigated in several studies.…”

“…Such effects, primarily concerned with improving or restoring endothelial function, inhibiting the proliferation and migration of vascular smooth muscle cells or reducing myocardial mass and fibrosis (5), have been demonstrated mainly for simvastatin, one of the most »popular« statins, with pleiotropic activity being confirmed clinically in a number of multicenter trials (6). The influence of other statins, including less lipophilic ones, has only been assessed in very few experimental studies (7)(8)(9)(10). Satoh et al (7) did not observe 28-d pravastatin administration to have any significant impact on the reduction of elevated right ventricular pressure (RVP) and cardiac hypertrophy in a mono-crotaline (MCT) rat model.…”