Abstract 20047: FXYD1 Protects Against Reactive Oxygen Species-Dependent Cardiac Remodelling and Fibrosis

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Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis.

Methods and Results:In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P<0.01), however interstitial fibrosis was absent. To stimulate cardiac interstitial fibrosis, Ang II (0.72 or 2.1 mg/kg/day) was infused via subcutaneous osmotic mini pump for 2 weeks. Ang II infusion resulted in elevated blood pressure (11 mmHg higher in FXYD1 KO mice vs. WT mice; P=0.01). This was associated with dose-dependent cardiac hypertrophy in FXYD1 KO mice (heart:body weight [mg/kg] sham: 4.8 +/- 0.3; AngII: 6.8 +/- 0.3; P<0.001) which was absent in WT mice (WT vs. KO P<0.001). High dose AngII caused moderate interstitial and perivascular fibrosis in WT mice which was worsened in FXYD1 KO mice (interstitial %: WT 24.3 +/- 5 vs. KO 34.3 +/- 8). Parallel changes in fibrosis markers including transforming growth factor beta 1, fibronectin and connective tissue growth factor expression were observed after only one week of AngII, with the greatest levels of all three markers occurring in Ang II infused FXYD1 KO mice.

Summary: This data defines a new role for FXYD1 as a protector of cardiac fibrosis characterized by elevated ROS. Although the causal relationship needs further study, preliminary data indicate that FXYD1 likely protects against cardiac fibrosis by preventing redox modification and subsequent inhibition of the Na+-K+ ATPase.

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