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

Marco Meloni, Betty Descamps, Andrea Caporali, Lorena Zentilin, Ilaria Floris, Mauro Giacca, Costanza Emanueli

Research output: Contribution to journalArticle (Academic Journal)peer-review

26 Citations (Scopus)

Abstract

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.
Translated title of the contributionNerve Growth Factor Gene Therapy using Adeno-Associated Viral Vectors Prevents Cardiomyopathy in Type 1 Diabetic Mice
Original languageEnglish
Pages (from-to)229 - 240
Number of pages12
JournalDiabetic Medicine
Volume61
Issue number1
DOIs
Publication statusPublished - Jan 2012

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