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Previous Volume 342:626-633 March 2, 2000 Number 9 Next

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ABSTRACT

Background When the myocardium is deprived of blood, a process of ischemia, infarction, and myocardial remodeling is initiated. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating early cellular responses to hypoxia. We investigated the temporal and spatial patterns of expression of the subunit of HIF-1 (HIF-1) and VEGF in specimens of human heart tissue to elucidate the early molecular responses to myocardial hypoxia.

Methods Ventricular-biopsy specimens from 37 patients undergoing coronary bypass surgery were collected. The specimens were examined by microscopy for evidence of ischemia, evolving infarction, or a normal histologic appearance. The specimens were also analyzed with the reverse-transcriptase polymerase chain reaction for HIF-1 and VEGF messenger RNA (mRNA) expression and by immunohistochemical analysis for the location of the HIF-1 and VEGF proteins.

Results HIF-1 mRNA was detected in myocardial specimens with pathological evidence of acute ischemia (onset, <48 hours before surgery) or early infarction (onset, <24 hours before surgery). In contrast, VEGF transcripts were seen in specimens with evidence of acute ischemia or evolving infarction (onset, 24 to 120 hours before surgery). Patients with normal ventricles or evidence of infarction in the distant past had no detectable levels of either VEGF mRNA or HIF-1 mRNA. HIF-1 immunoreactivity was detected in the nuclei of myocytes and endothelial cells, whereas VEGF immunoreactivity was found in the cytoplasm of endothelial cells lining capillaries and arterioles.

Conclusions An increase in the level of HIF-1 is an early response to myocardial ischemia or infarction. This response defines, at a molecular level, one of the first adaptations of human myocardium to a deprivation of blood. HIF-1 is a useful temporal marker of acutely jeopardized myocardium.

Source Information

From the Division of Cardiothoracic Surgery (S.H.L., R.E., S.W.J., P.A.T.), the Department of Pathology (P.L.W.), and the General Clinical Research Center (R.D.), University of California, San Diego; and the Department of Pathology, Veterans Affairs Medical Center, San Diego (P.L.W.).

Address reprint requests to Dr. Thistlethwaite at the Division of Cardiothoracic Surgery (8892), University of California, San Diego, 200 W. Arbor Dr., San Diego, CA 92103-8892, or at pthistlethwaite{at}ucsd.edu.

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