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  • Title: Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse.
    Author: Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, Thistlethwaite PA.
    Journal: J Am Coll Cardiol; 2005 Dec 06; 46(11):2116-24. PubMed ID: 16325051.
    Abstract:
    OBJECTIVES: The aim of this research was to test whether constitutive expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) 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-1alpha expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the HIF-1alpha gene under the control of the alpha-myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in HIF-1alpha 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-1alpha 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-1alpha-expressing animals compared to control animals. CONCLUSIONS: These observations suggest the involvement of HIF-1alpha 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.
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