Protective effects of INSL6 on heart failure

Background: The insulin/IGF/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. Methods and Results: Insl6-deficient (Insl6-KO) 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-KO mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation hypertrophy. Cardiac dysfunction in the Insl6-KO 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 Lxr/ Rxr signaling is activated in the isoproterenol-challenged hearts treated with INSL6 protein. Conclusions: 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.

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Maruyama S, Wu CL, Yoshida S, Zhang D, Li PH, Wu F, Parker Duffen J, Yao R, Jardin B, Adham IM, Law R, Berger J, Di Marchi R, Walsh K