Disrupted Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats

Abstract

The 2015 American Heart Association scientific statement has advocated for sex- specific research to understand the paradoxically higher sensitivity of women to type 2 diabetes mellitus (T2DM)-associated cardiovascular morbidity and mortality. The primary goal of this study was to address this need by elucidating the mechanisms by which these females lose inherent cardioprotection and become more susceptible to detrimental cardiovascular-related outcomes than males. The central hypothesis of this study was "estrogen (E2) exacerbation of diabetes-evoked disruption of cardiac adiponectin (APN)-connexin 43 (Cx43) signaling underlies heightened myocardial dysfunction in diabetic females". The study provides novel data on the modulation of the cardiac E2-APN-Cx43 axis and its critical role in maintaining a delicate redox balance in cardiomyocytes, how this cardioprotective signaling becomes detrimental in T2DM, and identified a molecular target for developing potential pharmacological interventions for diabetic females. Our findings demonstrate that E2 exacerbates female autonomic and cardiac dysfunction in a rodent model of T2DM, increasing left ventricular (LV) mass and Tau as well as decreasing LVDP, dP/dtmax, dP/dtmin, contractility index (CI) and fractional shortening (FS). Additionally, the restoration of the APN-Cx43 signaling axis via a small molecule APN agonist virtually reverses all of these cardiac dysfunction parameters as well as mitigates detrimental molecular alterations and a proinflammatory milieu in all female rats by restoring cardiac levels of Cx43, decreasing heme oxygenase 1 (HO-1), tumor necrosis factor (TNF) [alpha] and circulating levels of asymmetric dimethylarginine (ADMA). The research project replicates the unexplained paradoxically higher mortality risk in women and provides novel mechanisms for this cardiovascular health problem. Collectively, these findings support the hypothesis and proposed underlying mechanism and further demonstrations that the restoration of Cx43 emerges as a promising novel target in diabetic cardiovascular disease for the development of future therapeutics for women.