Sex-related dimorphic response of HIF-1 alpha expression in myocardial ischemia

Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H957-64. doi: 10.1152/ajpheart.00580.2005. Epub 2006 Apr 7.

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays a role in a number of cell-protective pathways after ischemia. There are clear sex-related differences in the remodeling process, and hearts from males tend to dilate in response to pathological loads and ischemia to a greater degree than do hearts from females. Thus we hypothesized that there would be a sex-related dimorphic response of HIF-1 alpha to an ischemic event. Male and female rats were euthanized 5 and 24 h after coronary ligation (M-MI and F-MI; MI, myocardial ischemia), and HIF-1 alpha expression was determined by immunohistochemistry, Western blot, and quantitative RT-PCR. Sham-operated male and female animals served as controls (M-SH and F-SH). In the ischemic area, histochemical analysis at 5 h showed that HIF was expressed in 33% of cell nuclei in M-MI and in 55% in F-MI. At 24 h, HIF expression increased to 49% in M-MI and to 82% in F-MI (P < 0.05 vs. SH and also M-MI vs. F-MI). This difference was not only statistically significant between the two sexes at 24 h but also within each sex at 5 and 24 h after ligation. Western blots confirmed that, at 24 h after ischemia, HIF protein increased significantly in both male and female hearts relative to sham-operated animals but that the increase in females was 60% greater than that seen in males. mRNA expression of HIF was significantly increased at 24 h in F-MI versus M-MI and sham-operated animals. Expression of downstream HIF target genes (heme oxygenase and brain natriuretic peptide) was increased in proportion to the levels of HIF expression. These data suggest a novel cellular mechanism to explain the sex-related dimorphic response to ischemia and also the possibility that exogenous modulation of HIF might represent a new therapeutic approach to preventing left ventricular remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Female
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Hypoxia-Inducible Factor 1 / biosynthesis*
  • Immunohistochemistry
  • Male
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / pathology
  • Myocardium / metabolism
  • Nitroimidazoles / pharmacology
  • RNA / biosynthesis
  • RNA / genetics
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sex Characteristics
  • Ventricular Remodeling / physiology

Substances

  • Hypoxia-Inducible Factor 1
  • Nitroimidazoles
  • pimonidazole
  • RNA