DISTINCT CARDIAC CONNEXIN-43 EXPRESSION IN HEMODYNAMICALLY UPLOADED AND UNLOADED HEART MAY IMPACT VULNERABILITY TO MALIGNANT ARRHYTHMIAS

Abstract

Objective: Experimental and clinical studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity to cardiac arrhythmias. While these are rare in conditions resulting in myocardial atrophy, such as hypothyroidism or type-1 diabetes mellitus (T1DM). One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cardiac cell-to-cell coupling for electrical signal propagation that induce contraction. We aimed to explore abundance of Cx43 protein and its cardiomyocyte topology in hemodynamically uploaded hypertrophied versus unloaded hypotrophic cardiac phenotype. Design and method: Analysis were performed in left ventricular tissue of adult male rats of following groups: 1. spontaneously hypertensive rat (SHR); 2. normotensive Wistar Kyoto rats (WKY) treated for 8-weeks with L-thyroxine (0.15 μg/kg, i.v.) to induce hyperthyroid status; 3. WKY rats treated with methimazol (0.05% solution, p.o.) to induce hypothyroid status; 4. WKY rats treated with strepotozotocin (50mg/kg, i.p.) to induce T1DM. Animals were compared with non-treated normotensive control rats. Results: Comparing to healthy non-treated rats there was a decrease of total myocardial Cx43 protein and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced abnormal localisation of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and T1DM rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKC epsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Conclusions: Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of uploaded and unloaded heart to malignant arrhythmias. It suggests that hemodynamically overloaded heart might benefit from interventions promoting unloading. This research was supported by VEGA grants 2/0002/20, 2/0006/23, Slovak Research and Development Agency under the Contract no. 21-0410