Relaxin reverses maladaptive remodeling of the aged heart through Wnt-signaling

• Published in: Scientific reports Vol. 9; no. 1; pp. 18545 - 12
• Main Authors: Martin, Brian, Gabris, Beth, Barakat, Amr F., Henry, Brian L., Giannini, Marianna, Reddy, Rajiv P., Wang, Xuewen, Romero, Guillermo, Salama, Guy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2019; Nature Publishing Group
• Subjects: 13; 13/1; 13/51; 13/95; 14; 14/19; 14/63; 38; 631/443/7; 631/80/86/2372; 82; Adult; Age Factors; Aged; Aging; Animals; Atrial Fibrillation - pathology; Atrial Fibrillation - physiopathology; Atrial Fibrillation - prevention & control; Cardiac muscle; Cardiovascular diseases; Cells, Cultured; Collagen; Connexin 43; Dkk1 protein; Fibrillation; Fibroblasts; Fibrosis; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Healthy Aging - pathology; Humanities and Social Sciences; Humans; Insulin; Isolated Heart Preparation; Localization; Male; multidisciplinary; Myocardium - cytology; Myocardium - pathology; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Primary Cell Culture; Pyridines - pharmacology; Pyrimidines - pharmacology; Rats; Relaxin; Relaxin - administration & dosage; Relaxin - metabolism; Rodents; Science; Science (multidisciplinary); Sodium channels (voltage-gated); Ventricle; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology; Wnt protein; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - physiology; Wnt1 Protein - administration & dosage; Wnt1 Protein - metabolism; β-Catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-53867-y

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 (EC 50  = 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.