Abstract 2099: AAV9-Wnt11 Gene Therapy Improves Cardiac Recovery After Myocardial Infarction by Modulating the Inflammatory Response
Background: Wnt signaling regulates multiple events in development and disease. Recent data suggest a relationship between a noncanonical Wnt signaling cascade and the regulation of inflammation in pathogenic disorders.
Objective: To investigate the effect of myocardial Wnt11 gene therapy on cardiac recovery after acute myocardial infarction (MI).
Methods: The effect of Wnt11 gene therapy in MI was examined in a murine GFP- bone-marrow-transplantation (BMT) MI model. GFP-BMT mice received single intravenous injections of either AAV9-Wnt11 or a control virus (AAV9-LacZ) one week before MI induction. Transgene expression and tissue distribution were assessed at multiple time points by RNA and protein analysis. Cardiac function was evaluated by echocardiography 1, 14, 28, and 56 days after MI. Fibrotic area was examined by Sirius red staining. Incorporation of BM MNCs into the ischemic area was examined immunohistochemically.
Results: Intravenous injection of AAV9-Wnt11 resulted in efficient, durable, and relatively cardiac-specific Wnt11 expression. Survival was significantly greater among Wnt11-treated mice than among control-treated mice (100% Wnt 11 vs 56.3% control, p<0.05), and Wnt11-treated mice also displayed significantly greater cardiac ejection fractions (23.6% Wnt11 vs 13.1% control, p<0.0001) and cardiac output (27.7 ml/min Wnt11 vs 19.4 ml/min control, p<0.001). Histological analyses found markedly decreased inflammatory-cell infiltration into the infarct area and adjacent, intact myocardium and less fibrous tissue formation in the non-infarct zone (1.57% wnt11 vs 2.89% control, p<0.005) in the Wnt11 group vs. control mice. RNA analysis confirmed that expression of inflammatory markers TNF-alpha and IL-1beta was significantly lower in Wnt11-treated animals.
Conclusions: This is the first report to implicate Wnt11 signaling in survival after MI. The present study suggests that Wnt11 gene therapy produces beneficial effects on cardiac function and survival after MI by modulating the inflammatory response after ischemic injury.