Downregulation of Cytosolic Connexin-43 in Left Ventricular Myocardium of Dogs with Chronic Heart Failure and Recovery After Treatment with #3-Adrenergic Receptor Antagonist

Document Type

Conference Proceeding

Publication Date

11-3-2025

Publication Title

Circulation

Keywords

HFrEF, Arrhythmias, Arrhythmias, treatment of, Connexin, Beta-blocker, Cardiovascular System & Cardiology

Abstract

Background: Cytosolic Connexin-43 (Cx43) plays a crucial role in the formation of gap junctions. Proper levels, localization, function, and interactions of Cx43 with other proteins are vital for maintaining electrical coupling between cardiomyocytes. A reduction in Cx43 protein levels in heart failure (HF) can lead to ventricular arrhythmias and sudden death. In the failing heart, β3 adrenergic receptors (ARs) are upregulated, a maladaptation that can lead to downregulation of Cx43. We previously showed that treatment of HF dogs with a β3-AR antagonist (APD418) improves LV systolic function.Hypothesis: The present study tested the hypothesis that 1) Cx43 protein levels are decreased in LV myocardium of dogs with HF and 2) treatment with a β3-AR antagonist (APD418) restores Cx43 protein levels. Studies were performed in LV myocardium of dogs with coronary microembolization-induced HF. In addition to marked LV dysfunction, the model, as in humans with HF, manifests spontaneous ventricular arrhythmias and sudden death.Methods: Studies were performed in LV tissue from 14 dogs with HF (LV EF ~35%) that were randomized to receive a 6-hour intravenous infusion of APD418 (4.224 mg/kg, n=7) or vehicle (0.9% NaCl, n=7). LV tissue from 7 normal healthy (NL) dogs served as controls. Cytosolic fractions were isolated from LV myocardium, and Cx43 protein levels were quantified with Western blotting using a dog specific monoclonal antibody. Housekeeping protein (cytosolic GAPDH) was used as a loading control. Band intensities were expressed in densitometric units (du).Results: Cytosolic GAPDH were unchanged between NL and HF dogs. Compared to NL dogs, vehicle treated HF dogs showed significantly reduced Cx43 levels (0.97 ± 0.05 vs. 2.98 ± 0.46 du, p<0.05). Treatment with APD418 significantly increased Cx43 levels compared to vehicle controls (1.82 ± 0.49 vs. 0.97 ± 0.05 du, p < 0.05).Conclusion: Cytosolic Cx43 levels are reduced in LV myocardium of dogs with HF; an abnormality that can trigger ventricular arrhythmias. Treatment with the β3-AR antagonist APD418 improves Cx43 protein levels. In addition to improving LV systolic function in HF, APD418 may potentially act to limit the development of life-threatening ventricular arrhythmias.

Volume

152

Issue

SUPPL_3

First Page

1

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