Faculty Collaboration Database

Sex-related dimorphic response of HIF-1 alpha expression in myocardial ischemia. Am J Physiol Heart Circ Physiol 2006 Aug;291(2):H957-64

Date

04/11/2006

Pubmed ID

16603692

DOI

10.1152/ajpheart.00580.2005

Scopus ID

2-s2.0-33746826853 (requires institutional sign-in at Scopus site)   27 Citations

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.

Author List

Zampino M, Yuzhakova M, Hansen J, McKinney RD, Goldspink PH, Geenen DL, Buttrick PM

MESH terms used to index this publication - Major topics in bold

Animals
Female
Gene Expression
Hypoxia-Inducible Factor 1
Immunohistochemistry
Male
Myocardial Ischemia
Myocardium
Nitroimidazoles
RNA
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Sex Characteristics
Ventricular Remodeling