Description

Pingping Xianga, Andrew V Schallyb, Hong Yua

aDepartment of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; bDepartment of Medicine, Miller School of Medicine, University of Miami, Veterans Affairs Medical Center, Miami, FL

Aim: Diastolic dysfunction is a characteristic of aged hearts. The agonists of growth hormone-releasing hormone (GHRH-A) exhibit several favorable effects on heart function. Here we assessed the effects of GHRH-A MR409 on heart function and systemic parameters in aged mice.

Methods and Results: Starting at the age of 15 months, mice were subcutaneously injected daily with MR409 (100ug/mouse) or vehicle (n=7 each). Echocardiography and body weights were measured at baseline and 5 months after treatment. Mice treated with MR409 for 5 months showed significantly improved ejection fraction and attenuated hypertrophy, increased exercise activity, and healthier hair growth in comparison with the controls. No changes in body weight were observed after the treatment. In studies in vitro, senescence levels were detected with ꞵ-gal staining in the doxorubicin-treated H9C2 cardiac myoblasts, neonatal cardiomyocytes (NRCM) or endothelial cells (EC) after 2 or 10 passages, respectively. When cultured with MR409, significantly fewer ꞵ-gal positive cells were observed as compared with control cells. Cell cycle associated protein p21 was reduced in all MR409-treated cells (H9C2, NRCM and EC). Reactive oxygen species in Dox-treated H9C2 cells were reduced when cultured with MR409. Electron microscopy showed that mitochondrial morphology was preserved in the Dox-treated H9C2 cells upon cultures with MR409 while it was damaged in control cells after Dox treatment. MR409 also improved cellular ATP production and oxygen consumption rate of Dox-treated H9C2.

Conclusion: GHRH-A can rejuvenate aged mice in aspects of heart function, exercise capacity, hair growth, cellular energy production and senescence biomarkers.