Abstract 162: Influence of Age and Ischemia on Cardiac Subsarcolemmal and Interfibrillar Mitochondria in a Novel Model of Estrogen Deficiency
Altered mitochondrial respiration (MR) and calcium retention capacity (CRC) are proposed cardiac cell death mechanisms exacerbated by aging in males. The present study aimed, for the first time, to determine changes in mitochondrial subpopulation function with age and ischemia/reperfusion (I/R) injury in the female heart. A novel model to recapitulate human menopause/age interactions was used in F344 female rats ovariectomized (OVX) at 15mo and studied at 24mo (MO OVX; n=15), vs adult (6mo; n=18). MR and CRC were assessed in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria following in vivo coronary artery ligation (CAL; 31 min I and 10 min R) or sham. State 3 MR energized by either complex I (CI) or complex II (CII) substrates was selectively reduced by age in SSM (p<.02), and by I/R in IFM (p<.05). The I/R-dependent decrease in CRC was 64% (18 vs 29.5) greater in MO OVX vs. adult IFM, suggesting earlier mitochondrial permeability transition pore (MPTP) opening. At CI, but not CII, cyclosporine A (CsA) enhanced CRC 20% (103 vs 86) more in SSM and 75% (98 vs 56) more in IFM from adult compared to MO OVX, suggesting reduced protective efficacy with age and MPTP involvement. Additionally, mitochondrial cyclophilin D increases with age, while cytoplasmic RIP1 is increased with age and I/R further implicating the MPTP mechanism and link with programmed necrosis in the aged female heart. In contrast to males, our data suggest a sex-specific phenotype whereby reductions in both SSM and IFM dynamics may play an additive role in the enhanced susceptibility to I/R injury and myocardial infarction in the aged female heart, which remains the leading cause of death in older women.
Author Disclosures: A.M. Garvin: None. N.C. Aurigemma: None. D.H. Korzick: None.
- © 2015 by American Heart Association, Inc.