Abstract 15335: Sex-Specific Cardiomyocyte Death in Heart Failure due to Sex-Specific Calcium Remodeling
L-type calcium (Ca2+) channels (LTCCs) play a key role in mitochondrial Ca2+ uptake, which may result in mitochondrial depolarization and metabolic collapse. Both apoptosis and necrosis occur in a sex-specific manner in heart failure (HF). However, the underlying mechanisms are unknown. We hypothesized significant sex differences in the cardiac transcriptome of end-stage non-ischemic dilated cardiomyopathy (DCM) patients. We compared left ventricular (LV) samples of age- and medication-matched male (n = 5) and female (n = 5) DCM patients with male (n = 10) and female (n = 8) controls by genome-wide expression profiling. Single gene differential analysis identified 4273 transcript clusters regulated in male, 1344 in female and 2817 in both male and female LVs (adjusted P < 0.01). Pathway analysis (adjusted P < 0.05) revealed induction of ECM-receptor interaction and several inflammatory pathways in male LVs, while oxidative phosphorylation and proteasome pathways were repressed. In female LVs, the Wnt and Hedgehog signaling pathways were induced, while the mTOR signaling pathway was repressed. Ca2+ signaling pathway was induced in both sexes. However, male LVs had a significantly higher induction of ca. 30% of genes encoding ion channels, accessory beta subunits and regulatory proteins than female LVs. Next, we isolated ventricular myocytes (VMs) from DCM patients and measured sarcoplasmic reticulum (SR) Ca2+ load and L-type Ca2+ current (ICa,L) by patch-clamp. While there were no sex differences in SR Ca2+ load, there was a 2-fold increase in ICa,L density in male vs. female VMs (n = 6-8 cells/group; each cell originated from a different individual; P < 0.05). The cytosolic release of cytochrome c was significantly higher in male than female LVs (P < 0.05). In view of that the anti-apoptotic protein BCL2 is involved in reducing recruitment of LTCCs, which in turn prevents mitochondrial Ca2+ overload, we found significantly higher BCL2 protein levels in female than male LVs (P < 0.05). Ca2+-mediated dephosphorylation of pyruvate dehydrogenase was higher in male than female LVs (P < 0.01) indicating more Ca2+ present in male mitochondria. We conclude that sex-specific regulation of Ca2+ homeostasis may account for sex differences in apoptosis and necrosis in HF.
Author Disclosures: G. Kararigas: None. C.E. Molina: None. H. Summer: Employment; Significant; Bayer. I. Baczko: None. S. Golz: Employment; Significant; Bayer. V. Regitz-Zagrosek: None.
- © 2014 by American Heart Association, Inc.