Abstract
Healthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases. Relaxin, an insulin-like hormone, suppresses atrial fibrillation, inflammation and fibrosis in aged rats but the mechanisms-of-action are unknown. Here we show that relaxin treatment of aged rats reverses pathological electrical remodeling (increasing Nav1.5 expression and localization of Connexin43 to intercalated disks) by activating canonical Wnt signaling. In isolated adult ventricular myocytes, relaxin upregulated Nav1.5 (EC50 = 1.3 nM) by a mechanism inhibited by the addition of Dickkopf-1. Furthermore, relaxin increased the levels of connexin43, Wnt1, and cytosolic and nuclear β-catenin. Treatment with Wnt1 or CHIR-99021 (a GSK3β inhibitor) mimicked the relaxin effects. In isolated fibroblasts, relaxin blocked TGFβ-induced collagen elevation in a Wnt dependent manner. These findings demonstrate a close interplay between relaxin and Wnt-signaling resulting in myocardial remodeling and reveals a fundamental mechanism of great therapeutic potential.
Highlights
Healthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases
These effects were linked to increased expression of the voltage-gated sodium channel Nav1.5, increased current (INa), and a marked decrease in fibrosis[5]
Inhibition of Wnt signaling by Dkk[1] significantly blocked RLX (Fig. 6f–j) and Wnt1’s (Fig. 6Bk–o) effects on Nav1.5 expression. These results strongly suggest that, contrary to the effects reported in neonate rat ventricular www.nature.com/scientificreports cardiomyocytes (NRVM), canonical Wnt signaling in adult cardiomyocytes increases Nav1.5 expression
Summary
Healthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases. We show that relaxin treatment of aged rats reverses pathological electrical remodeling (increasing Nav1.5 expression and localization of Connexin[43] to intercalated disks) by activating canonical Wnt signaling. We previously showed that the hormone relaxin (RLX) suppressed AF in aged (24-months old) rats by increasing conduction velocity (CV) of atrial action potentials[5]. These effects were linked to increased expression of the voltage-gated sodium channel Nav1.5, increased current (INa), and a marked decrease in fibrosis[5]. Wnt3a suppressed Nav1.5 expression in NRVM11, whereas activation of canonical Wnt signaling by other means increased Nav1.5 and Connexin-43 (Cx43), and reduced ventricular ectopic beats in NRVM, 3-week and 6-month old mouse models of arrhythmogenic cardiomyopathy[15,16,17]. In ventricles of RLX treated rats, the slope of the restitution kinetics curve becomes less steep than for untreated animals which suggests a decrease in arrhythmia vulnerability (Fig. 1Ab)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
