Simvastatin protects heart function and myocardial energy metabolism in pulmonary arterial hypertension induced right heart failure

• Published in: Journal of bioenergetics and biomembranes 2021-02, Vol.53 (1), p.1-12
• Main Authors: Tang, Bi, Kang, Pinfang, Zhu, Lei, Xuan, Ling, Wang, Hongju, Zhang, Heng, Wang, Xiaojing, Xu, Jiali
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animal Anatomy; Animal Biochemistry; Animals; Biochemistry; Bioorganic Chemistry; Calcium-binding protein; Calmodulin; Chemistry; Chemistry and Materials Science; Congestive heart failure; Energy metabolism; Energy Metabolism - drug effects; Energy reserves; Etiology; Heart failure; Heart Failure - drug therapy; Heart Failure - etiology; Heart function; Hemodynamics; Histology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypertension; Male; Metabolism; Monocrotaline; Morphology; Myocardium; Organic Chemistry; Pulmonary Arterial Hypertension - complications; Pulmonary Arterial Hypertension - drug therapy; Pulmonary hypertension; Rats; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Smad protein; Smad2 protein; Smad7 protein; Ventricle
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-020-09867-z

The favorable effect of simvastatin on pulmonary arterial hypertension (PAH) has been well defined despite the unknown etiology of PAH. However, whether simvastatin exerts similar effects on PAH induced right heart failure (RHF) remains to be determined. We aimed to investigate the function of simvastatin in PAH induced RHF. Rats in the RHF and simvastatin groups were injected intraperitoneally with monocrotaline to establish PAH-induced RHF model. The expression of miR-21-5p in rat myocardium was detected and miR-21-5p expression was inhibited using antagomiRNA. The effect of simvastatin on hemodynamic indexes, ventricular remodeling of myocardial tissues, myocardial energy metabolism, and calmodulin was explored. Dual-luciferase reporter system was used to verify the binding relationship between miR-21-5p and Smad7. In addition, the regulatory role of simvastatin in Smad7, TGFBR1 and Smad2/3 was investigated. Simvastatin treatment improved hemodynamic condition, myocardial tissue remodeling, and myocardial energy metabolism, as well as increasing calmodulin expression in rats with PAH-induced RHF. After simvastatin treatment, the expression of miR-21-5p in myocardium of rats was decreased significantly. miR-21-5p targeted Smad7 and inhibited the expression of Smad7. Compared with RHF rats, the expressions of TGFBR1 and Smad2/3 in myocardium of simvastatin-treated rats were decreased significantly. Collectively, we provided evidence that simvastatin can protect ATPase activity and maintain myocardial ATP energy reserve through the miR-21-5p/Smad/TGF-β axis, thus ameliorating PAH induced RHF.