PRECLINICAL STUDY
Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse
Masakuni Kido, MD*,
Lingling Du, MD*,
Christopher C. Sullivan, MS*,
Xiaodong Li, MD, PhD*,
Reena Deutsch, PhD ,
Stuart W. Jamieson, MB, FRCS* and
Patricia A. Thistlethwaite, MD, PhD*,*
* Division of Cardiothoracic Surgery, University of California, San Diego, San Diego, California.
Division of Biostatistics, University of California, San Diego, San Diego, California.
Manuscript received February 9, 2005;
revised manuscript received July 12, 2005,
accepted August 1, 2005.
* Reprint requests and correspondence: Dr. Patricia A. Thistlethwaite, Division of Cardiothoracic Surgery, University of California, San Diego, San Diego, California 92103-8892. (Email: pthistlethwaite{at}ucsd.edu).
OBJECTIVES: The aim of this research was to test whether constitutive expression of hypoxia-inducible factor 1-alpha (HIF-1 ) 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 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the HIF-1 gene under the control of the -myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in HIF-1 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 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–expressing animals compared to control animals.
CONCLUSIONS: These observations suggest the involvement of HIF-1 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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Abbreviations and Acronyms
| | EF = ejection fraction | | HIF-1 = hypoxia-inducible factor 1-alpha | | iNOS = inducible nitric oxide synthase | | LAD = left anterior descending coronary artery | | LV = left ventricle/ventricular | | PCR = polymerase chain reaction | | VEGF = vascular endothelial growth factor |
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