Abstract 15850: Sex-specific Transcriptional and Protein Regulation of Calcium Handling Leading to Sex Differences in Cardiomyocyte Death in Heart Failure
Mechanisms underlying sex differences in heart failure (HF) are poorly understood. Women appear to have better prognosis underlain by lower rates of apoptosis and necrosis than men. We hypothesized significant sex differences in left ventricular (LV) transcriptional and protein regulation of end-stage non-ischemic dilated cardiomyopathy (DCM) patients. We compared 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. Pathway analysis of genome-wide expression profiling (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 vs. female LVs. Patch-clamp recordings in isolated ventricular myocytes (VMs) from DCM patients showed that while there were no sex differences in sarcoplasmic reticulum Ca2+ load, there was a 2-fold increase in L-type Ca2+ current 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 vs. female LVs (P < 0.05). In contrast, the anti-apoptotic protein BCL2 was significantly higher in female vs. male LVs (P < 0.05). Ca2+-mediated dephosphorylation of pyruvate dehydrogenase was higher in male vs. female LVs (P < 0.01) indicating higher Ca2+ uptake in male vs. female mitochondria. Given the known reduction of the L-type Ca2+ channel activity by endothelial NO synthase (eNOS), we also show higher eNOS levels in female vs. male LVs (P < 0.05). We conclude that Ca2+ handling is the target of sex-specific transcriptional and protein regulation, which plays a major role in sex-specific mitochondrial Ca2+ uptake, thereby leading to sex differences in cardiomyocyte death in HF.
Author Disclosures: G. Kararigas: None. C.E. Molina: None. H. Summer: Employment; Significant; Employee. I. Baczko: None. S. Golz: Employment; Significant; Employee. V. Regitz-Zagrosek: None.
- © 2015 by American Heart Association, Inc.