Relaxin abrogates genomic remodeling of the aged heart

Vitam Horm. 2021:115:419-448. doi: 10.1016/bs.vh.2020.12.017. Epub 2021 Feb 18.

Abstract

"Healthy" aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in clinical trials, Relaxin-therapy for 2-days reduced mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short lifespan (2-3h) but long-lasting protective actions suggested that relaxin acts at a genomic level to reverse maladaptive remodeling in AF, HF and aging. Our recent studies showed that a 2-week treatment with Relaxin (0.4mg/kg/day) of aged (24months old F-344 rats) increases the expression of voltage-gated Na+ channels (mRNA, Nav1.5 and INa), connexin-43, abrogates inflammatory and immune responses and reverses myocardial fibrosis and cellular hypertrophy of the aged hearts. Relaxin acts directly at a wide range of cell types in the cardiovascular system that express its cognate GPCR receptor, RXFP1. RNA-seq analysis of young and aged hearts with and without Relaxin treatment revealed that "normal" aging altered the expression of ~10% of genes expressed in the ventricles, including: ion channels, components of fibrosis, hemodynamic biomarkers, immune and inflammatory responses which were reversed by Relaxin. The extensive cardiovascular remodeling caused by Relaxin was mediated through the activation of the Wnt/β-catenin signaling pathway which was otherwise suppressed by in adult cardiomyocytes intracellular by cytosolic Dickkopf1 (Dkk1). Wnt/β-catenin signaling is a mechanism that can explain the pleiotropic actions of Relaxin and the marked reversal of genomic changes that occur in aged hearts.

Keywords: Action potential (AP); Cellular hypertrophy; Conduction velocity (CV); Connexin 43; Fibrosis; G-protein-coupled receptor (GPCR); Insulin-like hormone; RLX receptor; Relaxin (RLX); Rxfp1; Voltage-gated sodium channels (I(Na)); Wnt/β-catenin signaling.

MeSH terms

  • Animals
  • Atrial Fibrillation* / drug therapy
  • Atrial Fibrillation* / pathology
  • Fibrosis
  • Genomics
  • Humans
  • Myocytes, Cardiac / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / metabolism
  • Relaxin* / metabolism
  • Relaxin* / pharmacology
  • Relaxin* / therapeutic use

Substances

  • Receptors, G-Protein-Coupled
  • Relaxin