Estrogen-Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies 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 Information East Carolina University, Brody School of Medicine, Department of Pharmacology and ToxicologyGraduate Student Funding This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperglycemia aggravates monocyte-endothelial adhesion in human umbilical vein endothelial cells from women with gestational diabetes mellitus by inducing Cx43 overexpression

“…Mugisho et al demonstrated that the inhibition of Cx43 could improve diabetic retinopathy. Furthermore, malfunctioning cardiac Cx43 signaling was found to play an important role in myocardial dysfunction in diabetic subjects, and the up-regulation of Cx43 in glomerular mesangial cells and diabetic mice was shown to ameliorate experimental diabetes-induced renal oxidative stress and fibronectin (27,28). For the first time, our research team clarified that Cx43 in hyperglycemia could induce monocyte-endothelial adhesion.…”

Heart Failure in Menopause: Treatment and New Approaches

“…In an attempt to investigate HFpEF, several animal models have been used including the bilateral oophorectomy (OVX) in rats, which provides a valuable model of hypertrophy and HF and allows the investigation of the role of estrogen-induced cardioprotection [ 30 ]. Comorbidities associated with female aging were evaluated in the OVX model which was also been linked to high blood pressure [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], volume overload [ 40 , 41 ], metabolic syndrome [ 42 , 43 , 44 ], type 2 diabetes (T2DM) [ 45 , 46 , 47 , 48 , 49 ] and stress [ 25 , 50 , 51 ].…”

“…E2 exacerbates myocardial dysfunction in ZDF rats by disrupting adiponectin signaling at cardiac level. In part, through the reduction of connexin-43 and phosphorylated survival molecules, ERK1/2 and phosphorylated AKT regulation in the heart [ 45 ], activation of pro-inflammatory pathways in the paraventricular nucleus occurs through the upregulation of ERα/ERβ receptors and adenosine A1/A2a receptors [ 49 ]. E2 paradoxically transforms into a pro-inflammatory hormone in the presence of oxidative stress [ 79 ], such as that induced by diabetes and obesity [ 80 ].…”

“…However, when OVX-DM2 are treated with E2, cardiac complications and mortality are similar to those observed in young females with T2DM. Reduction in AKT and ERK1/2 phosphorylation due to connexin 43 reduction are E2-dependent in OVX-DM2 since these proteins are not altered in estrogen depletion condition [ 45 ]. The proteins, AKT and ERK1/2, have been associated with protection of cardiomyocytes against apoptosis induced by oxidative stress [ 81 ], and their reduction would therefore contribute to the development of cardiac dysfunction.…”

Does Myocardial Atrophy Represent Anti-Arrhythmic Phenotype?

“…Meanwhile, depressed mechanical forces in atrophied heart may prevent abnormal Cx43 topology and contribute to a decreased susceptibility to developing malignant cardiac arrhythmia. In contrast, the accelerated disruption of cardiac adiponectin-Cx43 signalling is a molecular mechanism for exacerbated cardiac dysfunction and pro-arrhythmias in type-2 diabetic females [ 130 ].…”