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. (26th November 2018)

• Record Type: Journal Article
• Authors: Li, Tian; Shen, Yafeng; Su, Li; Fan, Xiaoyan; Lin, Fangxing; Ye, Xuting; Ding, Dianer; Tang, Ying; Yang, Yongji; Lei, Changhai; Hu, Shi
• Is Part Of: Journal of drug targeting. Volume 26:Number 10(2018)
• Page Start: 895
• Page End: 904
• Publication Date: 2018-11-26
• Subjects: Gene therapy -- post-myocardial ischaemia remodelling -- adeno-associated virus -- myocardial infarction; Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.1080/1061186X.2018.1450412
• Languages: English
• ISSNs: 1061-186X

Abstract

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 Ca 2+ 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 Ca 2+ handling and function. Moreover, PSEN1 gene transfer to failing cardiomyocytes reduced sarcoplasmic reticulum (SR) Ca 2+ leak, thereby restoring the diminished intracellular Ca 2+ transients and SR Ca 2+ 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.