Nerve Growth Factor Gene Therapy using Adeno-Associated Viral Vectors Prevents Cardiomyopathy in Type 1 Diabetic Mice

Objective: Diabetes is cause of cardiac dysfunction, reduced myocardial perfusion and ultimately heart failure. Nerve growth factor (NGF) exerts protective effects on the cardiovascular system. This study investigated if NGF gene therapy can prevent diabetic cardiomyopathy in mice. Research design and methods: Type 1 diabetes mellitus was induced in CD1 male mice by streptozotocin. Non-diabetic age-matched control male mice received the streptozotocin buffer. Murine NGF mRNA expression in the heart was measured by real-time RT-PCR at 12 weeks of diabetes. At 2 weeks of diabetes, cardiac expression of human NGF or β-Gal genes was induced by either intra-myocardial injection of adeno-associated virus vectors serotype 2 (AAV2) or systemic injection of AAV9. Non-diabetic mice received AAV2-β-Gal or AAV9-β-Gal. Results: Diabetes lowered the cardiac expression of endogenous NGF mRNA. A progressive deterioration of cardiac function and left ventricular chamber dilatation appeared in β-Gal–treated diabetic mice. At 12 weeks of diabetes, β-Gal–treated mice showed myocardial microvascular rarefaction, hypoperfusion, more interstitial fibrosis and increased apoptosis of endothelial cells and cardiomyocytes. NGF gene therapy using either AAV2 or AAV9 prevented diabetes-induced cardiac dysfunction, reduced cardiac apoptosis and preserved cardiac microvasculature and blood flow. Conclusions: AAV vectors-mediated myocardial NGF overexpression can prevent diabetesinduced cardiac dysfunction and myocardial microangiopathy. These results suggest the therapeutic potential of NGF for the prevention of cardiomyopathy in diabetic subjects.