Dysregulation of nuclear factor erythroid 2-related factor 2 signaling and activation of fibrogenic pathways in hearts of high fat diet-fed rats.

Abstract

High fat diet (HFD)-induced obesity adversely affects cardiac outcomes; however the effect of HFD consumption on myocardial remodeling and the underlying mechanisms are still elusive. This study aimed to examine the histological and molecular changes in cardiac tissue of HFD-fed rats. Eight-week old male Wistar rats were fed either HFD or normal chow diet for 16weeks and then assessed for changes in metabolic and cardiac homeostasis (n=10 each group). 16weeks on HFD resulted in obesity, dyslipidemia and altered glucose tolerance but no hypertension. Histological examination of Masson's trichrome stained-cardiac sections revealed massive fibrotic changes, while immunoblotting analysis showed higher expressions of collagens I and III, and fibronectin in cardiac tissue of HFD-fed rats. The expressions of transforming growth factor beta1 and the phosphorylation of its downstream target, Smad3, were significantly increased in cardiac tissue of HFD-fed rats. Activation of endothelial-mesenchymal transition was promoted in hearts of HFD-fed rats, as evidenced by down-regulation of platelet endothelial cell adhesion molecule-1, while upregulation of α-smooth muscle actin and vimentin. Consumption of HFD induced dysregulation of AMP-activated protein kinase/glycogen synthase kinase-3 beta signaling in cardiac tissue of rats. This was coupled with down-regulation of nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream targets in cardiac tissue of HFD-fed rats, as well as enhanced the oxidative stress and inflammatory burden. These results demonstrate that moderate-term consumption of HFD can enhance oxidative stress, induce inflammation, and activate the fibrogenic pathways in cardiac tissue of rats which stimulate fibrotic remodeling. Our findings may implicate the dysregulation of Nrf2 signaling as a putative mechanism for this effect.