Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

• Published in: Journal of the American Heart Association Vol. 7; no. 12
• Main Authors: Maruyama, Sonomi, Wu, Chia‐Ling, Yoshida, Sumiko, Zhang, Dongying, Li, Pei‐Hsuan, Wu, Fangzhou, Parker Duffen, Jennifer, Yao, Rouan, Jardin, Blake, Adham, Ibrahim M., Law, Ronald, Berger, Joel, Di Marchi, Richard, Walsh, Kenneth
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 10.06.2018; Wiley
• Subjects: Animals; anti‐fibrosis; anti–cardiac remodeling; Disease Models, Animal; Fibrosis; heart failure; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - prevention & control; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Liver X Receptors - genetics; Liver X Receptors - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardium - metabolism; Myocardium - pathology; Original Research; relaxin family protein; Retinoid X Receptors - genetics; Retinoid X Receptors - metabolism; Signal Transduction; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - pathology; Ventricular Dysfunction, Left - physiopathology; Ventricular Dysfunction, Left - prevention & control; Ventricular Function, Left; Ventricular Remodeling; heart failure; anti‐fibrosis; relaxin family protein; anti–cardiac remodeling
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.117.008441

The insulin/insulin-like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin-2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin-like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss-of-function and protein delivery methods. Insl6-deficient and wild-type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6-knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6-knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis-associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol-challenged hearts treated with INSL6 protein. Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II- and isoproterenol-induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.