Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat

• Published in: The Journal of heart and lung transplantation Vol. 29; no. 9; pp. 1058 - 1066
• Main Authors: Keränen, Mikko A.I., MD, Nykänen, Antti I., MD, PhD, Krebs, Rainer, MSc, Pajusola, Katri, PhD, Tuuminen, Raimo, MD, Alitalo, Kari, MD, PhD, Lemström, Karl B., MD, PhD
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2010
• Subjects: AAV; apoptosis; CAV; HIF-1α; ischemia; Surgery; apoptosis; CAV; HIF-1α; AAV; ischemia
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2010.05.021

Background Hypoxia-inducible factor-1 (HIF-1), a key transcription factor in hypoxia, affects a wide range of adaptive cell functions. We examined the kinetics of endogenous HIF-1α during acute and chronic rejection, and the effect of exogenous HIF-1α in chronically rejecting rat cardiac allografts. Methods Heterotopic cardiac transplantations were performed between major MHC-mismatched Dark Agouti and Wistar–Furth rats. Cyclosporine A (CsA) was used to prevent acute rejection in the chronic rejection model. The effect of HIF-1α overexpression was investigated by adeno-assocated virus 2 (AAV2)-mediated gene transfer of a constitutively stabilized form of mouse HIF-1α (AAV-HIF-1α). The analysis of allografts was based on histology, immunohistochemistry and quantitative reverse transcript–polymerase chain reaction (RT-PCR). Results Acute and chronic rejection significantly induced HIF-1α mRNA in rat cardiac allografts when compared with syngeneic controls. Immunohistochemistry localized significantly increased HIF-1α immunoreactivity to vascular smooth muscle cells, vascular endothelial cells, post-capillary venules and graft-infiltrating mononuclear inflammatory cells of the allograft, whereas expression in cardiomyocytes remained unchanged. Regression analysis revealed a linear correlation between the progression of cardiac allograft vasculopathy (CAV) and HIF-1α immunoreactivity in post-capillary venules and graft-infiltrating mononuclear inflammatory cells in chronically rejecting rat cardiac allografts. AAV-HIF-1α enhanced cardiomyocyte HIF-1α production and significantly reduced cardiomyocyte apoptosis and the development of CAV in chronically rejecting rat cardiac allografts. Conclusions We found that acute and chronic rejection increased HIF-1α mRNA and protein levels in rat cardiac allografts. On the other hand, cardiomyocyte-targeted HIF-1α gene transfer inhibited cardiomyocyte apoptosis and the development of CAV, suggesting a novel therapeutic strategy for HIF-1α in cardiac allografts.