Sex-related dimorphic response of HIF-1 alpha expression in myocardial ischemia.
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.
Zampino
Manuela
M
Section of Cardiology, Center for Cardiovascular Research, Univ. of Illinois at Chicago, 840 South Wood St, M/C 787, Chicago, IL 60612, USA.
Yuzhakova
Milana
M
Hansen
James
J
McKinney
Ronald D
RD
Goldspink
Paul H
PH
Geenen
David L
DL
Buttrick
Peter M
PM
D000818:Animals; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D020257:Ventricular Remodeling / Q000502:physiology
D051793:Hypoxia-Inducible Factor 1; D009593:Nitroimidazoles; C033815:pimonidazole; D012313:RNA