Hypoxia-inducible factor 1(HIF-1)plays a role in a number of cell protective pathways following ischemia.There are clear gender related differences in the remodeling process and hearts from males tend to dilate in response to pathologic loads and ischemia to a greater degree than hearts from females.Thus,we hypothesized that there would be a gender dimorphic response of HIF-1to an ischemic event.Male and female rats were sacrificed 5 and 24hrs following coronary ligation(M-MI and F-MI)and HIF-1expression 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 5hrs showed that HIF was expressed in 33%of cell nuclei in M-MI and in 55%in F-MI.At 24hrs HIF expression increased to 49%in M-MI and 82%in F-MI(p< 0.05 vs SH and also M-MI vs F-MI).This difference was not only statistically significant between genders at 24 hrs but also within gender at 5 and 24hrs after ligation.Western blots confirmed that at 24hrs after ischemia HIF protein increased significantly in both male and female hearts relative to sham animals but that the increase in females was 60%greater than that seen in males.mRNA expression of HIF was significantly increased at 24hrs in the F-MI vs M-MI and shams.Expression of downstream HIF target genes(Heme oxygenase and BNP)was increased in proportion to the levels of HIF expression.These data suggest a novel cellular mechanism to explain the gender dimorphic response to ischemia and also the possibility that exogenous modulation of HIF might represent a new therapeutic approach to preventing LV remodeling.