Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse

OBJECTIVES The aim of this research was to test whether constitutive expression of hypoxia-inducible factor 1-alpha (HIF-1 alpha) influences infarction size and cardiac performance after myocardial infarction. BACKGROUND A major question in clinical medicine is whether infarction size and border zone remodeling of the heart can be influenced by the overexpression of specific genes in the peri-infarction region. METHODS We investigated the role of constitutive HIF-1 alpha expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the HIF-1 alpha gene under the control of-myosin heavy chain promoter were constructed. Myocardial was produced by the a coronary ligation in HIF-1 alpha transgenic mice and control animals. Extent of infarction was then quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathologic analysis of heart samples in infarct, peri-infarct, and remote heart regions at serial time points. RESULTS Constitutive overexpression of HIF-1 alpha in the murine heart resulted in attenuated infarct size and improved cardiac function 4 weeks after myocardial infarction. Significantly, we found an increase in both capillary density as well as vascular endothelial growth factor and inducible nitric oxide synthase expression in peri-infarct and infarct regions in the hearts of constitutive HIF-1 alpha-expressing animals compared to control animals. CONCLUSIONS These observations suggest the involvement of HIF-1 alpha in myocardial remodeling and peri-infarct vascularization. Our results show that supranormal amounts of this peptide protect against extension of infarction and improve border zone survival in myocardial infarction.