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 (E2)-dependent cardioprotection, remain unknown. We hypothesized that the reliance of the healthy females’ hearts on augmented adiponectin (APN)-connexin43 (Cx43) signaling becomes paradoxically detrimental when disrupted by T2DM in an E2-dependent manner. We tested this hypothesis in high fat-low dose streptozotocin diabetic rats and their controls with the following designations: (a) sham operated (SO); (b) ovariectomized (OVX); (c) ovariectomized with E2 supplementation (OVX+E2); and (d) male. E2-replete (SO or OVX+E2) 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 to respective nondiabetic counterparts, the hearts of these E2-replete diabetic rats exhibited greater upregulation of cardiac estrogen receptor α (ERα) and reductions in Cx43 expression and in the phosphorylation levels of the survival molecules pERK1/2 and pAKT. While serum APN was reduced independent of sex and ovarian hormone status in all DM, cardiac APN was most drastically reduced in DM SO rats. The present translational findings are the first to implicate ovarian hormones/E2 in the exacerbated myocardial dysfunction in diabetic females, and to suggest a pivotal role for malfunctioning cardiac APN-Cx43 signaling in this sex/E2-specific clinical problem.