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Abstract 259: Resistin Accelerates Fibroblast-Myofibroblast Differentiation and Induces Myocardial Fibrosis


 Background:
 Cardiac fibrosis (CF) is a major cause of heart failure in patients with ischemic insult, obesity, and diabetes. CF, characterized by excessive deposition of extracellular matrix proteins and myofibroblast differentiation, leads to profound changes in ventricular architecture and geometry, and thereby reduces cardiac function. Resistin, an adipokine has been linked to obesity, insulin resistance and diabetes. Our previous findings have implicated resistin in CF, however the molecular mechanisms underlying this process are still unclear. In this study, we investigated whether resistin regulates the transdifferentiation of fibroblasts into myofibroblasts as well as the molecular pathways leading to resistin-induced fibrotic response.
 
 
 Methods:
 Fibroblast-to-myofibroblast differentiation was induced with resistin, TGFβ1 or FBS for 48hours in isolated cardiac fibroblasts from adult mouse and mouse embryonic fibroblasts (NIH3T3 cells). Resistin knockout mice were challenged with high fat diet for 16 weeks to stimulate cardiac lipotoxicity. Fibrotic response and markers were determined in harvested hearts.
 
 
 Results:
 Adult cardiac fibroblasts stimulated with resistin displayed increased fibroblast-to-myofibroblast differentiation, with significantly increased levels of collagen, fibronectin, and connective tissue growth factor. Mechanistically, we demonstrated that resistin promotes fibrogenesis via Jak-Stat and c-Jun signaling pathways, independently of TGFβ1. In-vivo study confirmed the role of resistin in cardiac fibrosis. Resistin knockout mice, when challenged with high fat diet to stimulate cardiac lipotoxicity, showed a decrease in fibrosis paralleled with reduced mRNA levels of various markers of fibrosis such as collagen, fibronectin and connective tissue growth factor compered to wild type hearts. A significant improvement in heart function was also observed in resistin knockout mice.
 
 
 Conclusions:
 To our knowledge, these findings are the first to demonstrate a role of resistin in the process of cardiac fibroblast-to-myofibroblast conversion through Jak-Stat and c-Jun signaling. These results bring new insights into the mechanisms by which resistin may contribute to cardiac fibrosis.
