Abstract 11509: Alterations in Cardiac BRCA1 Expression in Human Models of Ischemia and Reperfusion
BRCA1 is a critical gatekeeper of genome stability and limits DNA damage and apoptotic cell death. BRCA1 has recently been identified as an essential regulator of cardiac structure and function in experimental models of ischemic cardiomyopathy. Whether BRCA1 expression is altered in human cardiac tissues is unknown. We assessed BRCA1 expression in human immature and mature atria and ventricular samples in response to simulated or chronic ischemia. First, we obtained human atrial biopsies intra-operatively from patients before and after initiation of cardiopulmonary bypass and cardioplegic arrest (n=10). We report that human atrial tissues subjected to perioperative ischemia and reperfusion demonstrated 1.5 fold greater BRCA1 expression compared to those obtained prior to cardiopulmonary bypass and cardioplegic arrest (p<0.05). Second, to extend our observations to a model of chronic ischemic heart disease, we obtained ventricular biopsies from patients undergoing open heart surgery. BRCA1 protein levels in ventricular biopsies from patients undergoing valvular surgery without clinical signs and symptoms of ischemia (non-ischemic group, n=4) were compared to tissues from patients with documented coronary artery disease undergoing coronary artery bypass surgery (ischemic group, n=11). We report that human ventricular tissues from patients with ischemic heart disease demonstrated higher levels of BRCA1 (∼2.1 fold) compared to those from subjects without ischemic heart disease (p<0.05). Lastly, to evaluate whether BRCA1 up-regulation is specific to the developed vs. developing heart, we studied primary cultures of human fetal cardiomyocytes derived from normal hearts after elective pregnancy termination (gestational age 15-20 weeks). We report a significant (p<0.05) upregulation of total and phosphorylated BRCA1 in human fetal cardiomyocytes in response to hypoxia. We provide the first evidence that BRCA1 expression is upregulated in response to ischemia or hypoxia in the developed and developing human heart. These data extend the experimental data on the cardioprotective effects of BRCA1 and suggest that strategies aimed at augmenting BRCA1 bioactivity may represent a novel mechanism to limit ischemic cardiomyopathy.
- © 2011 by American Heart Association, Inc.