Cardiac adeno-associated virus 9-mediated delivery of nestin-640 prevents myocardial remodeling in a rodent model of post-ischemic heart failure

Purpose: We determined the long-term therapeutic effectiveness and safety of intramyocardial adeno-associated virus 9(AAV9)-mediated gene delivery of nestin-640 (Nest640) in a rodent model of post-ischemic heart failure. Nest640, a truncated form of intermediate filament Nestin, plays a critical role in modulating the sensitivity to oxidative stress induced cell death. Methods: We induced heart failure in twenty-one adult male Winstar rats by permanent ligation of the left descending coronary artery. After sixty minutes, the animals were subjected to intramyocardial injection of AAV9-Nest640 (1012, n=9) in the infarct border zone. AAV9-green fluorescent protein (AAV9-GFP, 1012, n=6) or saline treatment (PBS, n=6) served as control. Left ventricular (LV) structure and function was investigated by histology and echocardiography. Results: At 4 weeks both control groups showed a weak myocardial protein expression of Nestin in the infarct border zone related to progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-Nest640 treatment rescued LV ejection fraction compared to PBS (60.7+4.97 vs 37.13+2.2%, p , 0.05). In addition, the LV end-diastolic thickness was significantly preserved in the infarct border zone of AAV9-Nest640 compared to PBS (1.3+0.1 vs 0.7+0.07mm, p , 0.05). Consistent with this morpho-functional outcome, animals treated with AAV9-Nest640 showed LV infarct scar size significantly reduced by 40.6+7% compared to untreated animals. No differences were observed between PBS and AAV9-GFP rats. Histological analysis of the AAV9-Nest640 border regions showed a significant increase in the number of Nest640-negative/alpha-SMA-positive arterioles compared to PBS (17.9+1.4 vs 12+1vessels per mm2). Nest640 expression was restricted to cardiomyocytes, and apoptotic index of LV infarct border zone was significantly reduced by 50+1%. Rare ki67-positive cells were detected in each experimental group. Conclusions: Our results indicate that Nest640 gene delivery halts post-ischemic myocardial remodeling and preserves cardiac function by promoting both cardiomyocyte viability and arteriologenesis in rodent infarcted hearts.