Abstract 3288: Mitofusin 2 Inhibits Cardiac Fibroblast Proliferation and Collagen Synthesis Stimulated by Angiotensin II in Rat
Objective: Pathological cardiac hypertrophy/remodeling is always associated with abnormal growth of cardiac fibroblasts and collagen synthesis, progressing to heart failure. Mitofusin 2(Mfn2), which is a mitochondrial dynamin-related protein, vital in the mitochondrial energy supply, was down-regulated in cardiac hypertrophy. It has been shown that overexpression of Mfn2 may attenuate the cardiac hypertrophy in vitro. However, its role in cardiac fibroblasts has remained largely unknown. In this study, the potential role of Mfn2 in regulating cardiac fibroblasts proliferation and collagen synthesis was investigated.
Methods and results: Angiotensin II (Ang II) was given to SD rats by a subcutaneously implanted osmotic mini-pump for 14 days at a rate of 0.7 mg/kg/day. Then the replication-deficient adenoviral vectors encoding lacZ(AdLacZ) or rat Mfn2 gene (AdMfn2) were injected to the myocardium directly using a microinjector to transfer genes. Chronic AngII infusion caused concentric cardiac hypertrophy measured by echocardiography (sham:2.9±0.4, AngII:4.1±0.6 mg/g heart to body weight ratio), accompanied by enhancement of collagen levels in cardiac tissue (sham:177.9±26.4, AngII:232.7±54.9 μg/g the hydroxyproline content). Transfection with AdMfn2 decreased the cardiac collagen level (−18%), the mRNA levels of collagen I (−28%) and the ratio of collagen type I to collagen type III (−16%) when compared with AdLacZ group. In vitro, overexpression of Mfn2 decreased the fibroblast proliferation(−34%), DNA synthesis(−41%) and collagen synthesis(−81%) induced by Ang II utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 3H-thymidine incorporation, and 3H-proline incorporation. Western blot analysis showed that the phosphorylated-ERK1/2 (phospho-ERK) activated by AngII was decreased in Mfn2-overexpressed cardiac fibroblasts compared with controls.
Conclusion: Cardiac fibroblast proliferation, and collagen synthesis were reduced after overexpression of Mfn2, related to the inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2), suggesting that Mfn2 represents an attractive molecular target for attenuating cardiac fibrosis.