Cardiac adenovirus-associated viral Presenilin 1 gene delivery protects the left ventricular function of the heart via regulating RyR2 function in post-ischaemic heart failure

Abstract

Post-ischaemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca²⁺ and redox homeostasis at the cellular level caused by ischaemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischaemic heart failure. Adeno-associated viral PSEN1 gene delivery elevated PSEN1 protein expression in a post-infarction rat heart failure model, and this administration normalised the contractile dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca²⁺ handling and function. Moreover, PSEN1 gene transfer to failing cardiomyocytes reduced sarcoplasmic reticulum (SR) Ca²⁺ leak, thereby restoring the diminished intracellular Ca²⁺ transients and SR Ca²⁺ load. Moreover, PSEN1 gene transfer reversed the phosphorylation of RyR2 in failing cardiomyocytes. However, selective autophagy inhibition did not prevent the PSEN1-induced blockade of RyR2 degradation, making the participation of autophagy in PSEN1-associated RyR2 degradation unlikely. Our results established a role of the cardiac expression of PSEN1 with AAV9 vectors as a promising therapeutic approach for post-ischaemic heart failure.

Keywords:

• Gene therapy
• post-myocardial ischaemia remodelling
• adeno-associated virus
• myocardial infarction

Acknowledgements

We thank Y. Guo, J. Zhao, B. Li, J. Dai, H. Wang, and H. An for the critical support of the research; Y. Bao and Z. Zou (Changzheng Hospital Translational Medicine Center) for generous help of the research.

Disclosure statement

D.D. is employed by Pharchoice Therapeutics Inc., and is shareholder in Pharchoice Therapeutics Inc. No potential conflicts of interest were disclosed by the other authors.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [grant nos. 81773261 and 81602690]; Military Medicine Special grant of Second Military Medical University [grant no. 2017JS01], a General Financial Grant from the China Postdoctoral Science Foundation [grant no. 2016M593006] and postdoctoral scientific research funds of Second Military Medical University.