Estrogen-Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats

The reasons for the higher severity of type 2 diabetes (T2DM)-associated cardiomyopathy in women, despite their inherent estrogen (E-2)-dependent cardioprotection, remain unknown. We hypothesized that the reliance of the healthy females' hearts on augmented adiponectin (APN)-connexin 43 (Cx43) signaling becomes paradoxically detrimental when disrupted by T2DM in anE(2)-dependent manner. We tested this hypothesis in high-fat, low- dose streptozotocin diabetic rats and their controls with the following designations: 1) sham-operated (SO), 2) ovariectomized (OVX), 3) ovariectomized with E-2 supplementation (OVX + E-2), and 4) male. E-2-replete (SO or OVX + E-2) diabetic rats exhibited higher mortality and greater increases in left ventricular (LV) mass and reduced LV developed pressure, LV contractility, and fractional shortening but preserved ejection fraction. Further, compared with respective nondiabetic counterparts, the hearts of these E-2 -replete diabetic rats exhibited greater upregulation of cardiac estrogen receptor alpha and reductions in Cx43 expression and in the phosphorylation levels of the survival molecules extracellular regulating kinases 1/2 and phosphorylated AKT (pAKT). Whereas serum APN was reduced, independent of sex and ovarian hormone status in all DM rats, cardiac APN was most drastically reduced in DM SO rats. The present translational findings are the first to implicate ovarian hormones/E-2 in the exacerbated myocardial dysfunction in female diabetic subjects and to suggest a pivotal role for malfunctioning cardiac APN-Cx43 signaling in this sex/E-2-specific clinical problem.