DJ-1 Gene Therapy Opposes the Development of Ischemic Heart Failure

Background: DJ-1 is a cytoprotective protein that is activated in response to various pathological stimuli. The ability of DJ-1 to perform its cellular actions is dependent on a conformational change, as evidenced by previous findings that it is cleaved by oxidative stress and that this cleavage activates its cytoprotective function. Previously, we demonstrated that the loss of functional DJ-1 lead to the enhancement of myocardial infarction and exacerbation of cardiac dysfunction following the onset of acute myocardial ischemia-reperfusion (I/R) injury. Currently, it is not known if the gain of functional DJ-1 has cardioprotective effects. Here, we investigated if the delivery of the cleaved form of DJ-1 using a gene therapy approach protected against the development of ischemic-induced heart failure. Methods and Results: We generated a viral vector to express the active form of DJ-1 (AAV9-DJ1WTΔC). To test the efficiency, specificity, and dose-dependence of AAV9-mediated transduction, we injected increasing doses of AAV9-GFP into the femoral vein of mice. A dose-dependent increase in GFP levels was observed in the heart and our analysis found that the 2x10 11 vg/mL dose achieved maximal delivery to the heart with minimal delivery to other tissue. GFP-stained sections of heart indicated that a substantial proportion of cardiomyocytes expressed the transduced gene. Next, we evaluated the protein expression of the full-length and active form of DJ-1 2 weeks after the administration of AAV9-DJ1WTΔC. No changes in the expression of the full-length form of DJ-1 were observed, but a 2-fold increase in the active form of DJ-1 was observed. Finally, mice administered AAV9-DJ1WTΔC displayed significant less left ventricular dilatation, left ventricular dysfunction, and hypertrophy compared to the AAV9-Empty treated following mice 60 minutes of myocardial ischemia and 4 weeks of reperfusion. Conclusion: These results indicated that DJ-1 is an endogenous cytoprotective protein that protects against the development of ischemic heart failure. Importantly, these results demonstrate the feasibility of using a gene therapy approach to deliver the cleaved form of DJ-1 to the heart as a therapeutic strategy to protect against ischemic heart disease.