Increased expression of DRAM1 confers myocardial protection against ischemia via restoring autophagy flux.

BACKGROUND

DRAM1 (Damage-regulated autophagy modulator 1) was reported as one of the most important lysosome membrane protein that mediates the interaction between autophagosome and lysosome. Our aim was to investigate whether DRAM1 contributes to cardiac remodeling after acute myocardial infarction (AMI) and the underlying mechanisms.

METHODS AND RESULTS

Adenovirus harboring DRAM1 was injected in the peri-infarct zone in a rat model of AMI experimentally produced by permanent ligation of left anterior descending (LAD) coronary artery. Increased DRAM1 expression protected the cardiomyocytes from ischemia stress-induced autophagy flux obstacle and improved cardiac prognosis after AMI. DRAM1 overexpression attenuated the accumulation of autophagy substrate protein, LC3IIand p62/SQSTM1 obviously both in vivo and in vitro. An adenovirus harboring mRFP-GFP-LC3 showed that DRAM1 overexpression restored the autophagic flux by enhancing autophagosome conversion to autophagolysosome. Although Atg12 mRNA was up-regulated with DRAM1 overexpression the free Atg12 protein was decreased accompanied by increased Atg12-Atg5 conjugate both in vitro and in vivo. Of interest, immunoprecipitation assay showed that DRAM1 interacted with Atg7, but without direct interaction with Atg5 or Atg12. Notably, the effect of DRAM1 on autophagy flux and cardiomyocyte protection could be mitigated by Atg7 siRNA.

CONCLUSIONS

Our results indicated that DRAM1 protected cardiomyocytes from ischemia stress-induced autophagy flux obstacle and uncovered a novel DRAM1-Atg7-Atg12/Atg5 autophagy flux regulation pathway under conditions of myocardial ischemic stress.