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

Abstract

Women are diagnosed with type 2 diabetes (T2DM) at an increasing rate, and there is renewed interest in estrogen (E2) replacement therapy (ERT). It remains unknown if E2 contributes to the greater susceptibility of women to diabetes‐evoked myocardial dysfunction. In diabetic men and male animals, the formation of connexin43 (Cx43) hemichannels, at the expense of the physiological Cx43‐based gap junction domain, underlies myocardial dysfunctions. While Cx43 constitutes a promising therapeutic target for cardiovascular anomalies, its role and its modulation by adiponectin (APN) in diabetic females remain unknown. APN, an anti‐inflammatory adipokine with higher levels in females, is reduced in T2DM and coronary artery disease. Whether the higher APN‐Cx43 expression and signaling in healthy female hearts becomes paradoxically detrimental when disrupted by T2DM in an E2‐dependent manner has not been studied. Therefore, we tested the hypothesis that E2 exacerbation of diabetes‐evoked disruption of cardiac APN‐Cx43 signaling underlies heightened myocardial dysfunction in diabetic females.We examined eight groups of Wistar rats (n=8 each); divided into DM or control groups with the following designations: i. sham operated (SO), ii. ovariectomized (OVX), iii. ovariectomized with E2 supplementation (OVX+E2), and iv. male. Females underwent OVX or sham surgery at week 0, and DM was induced with a high fat diet (45%), low‐dose streptozotocin regimen (2 injections, one week apart; 35 mg/kg; I.P.). OVX rats received subcutaneous implants of E2 (OVX+E2) or vehicle (OVX). Over the 10‐week study, weekly body weight, food intake and tail cuff blood pressure were collected along with biweekly echocardiography (starting at week 0). Following final echocardiography, IV glucose tolerance testing, femoral and left ventricular (LV) catheterization were conducted for integrative hemodynamic measurements. Results showed significant increases in LV mass and tau, and decreases in LV developed pressure, LV contractility and fractional shortening in the diabetic female E2‐replete groups (SO or OVX+E2), compared to respective nondiabetic controls or E2‐depleted (OVX or male) rats. Biochemical analysis of cardiac tissue (western blots) showed upregulated estrogen receptor α (ERα) expression in all DM groups, with downregulation of APN receptor 1 (AdipoR1) in E2‐depleted DM groups (OVX and male). Cx43 expression was reduced (P<0.05) in E2‐replete DM females (SO or OVX+E2). The present novel findings are the first to implicate E2 in the exacerbated myocardial dysfunction in diabetic females, and to discern malfunction in cardiac APN‐Cx43 signaling as an underlying mechanism for this sex/E2‐specific problem.Support or Funding InformationEast Carolina University, Brody School of Medicine, Department of Pharmacology and ToxicologyGraduate Student FundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.