Abstract 16482: Ablation of FN14 Reduces Fibrosis in Pulmonary Arterial Hypertension Rescuing Heart Function
Right ventricular failure is the leading cause of death in pulmonary arterial hypertension (PAH), which is preceded with sustained right ventricular hypertrophy (RVH) and fibrosis. The molecular mechanisms of RV dysfunction in PAH are poorly understood. Thus it is important to elucidate mechanisms controlling RVH, fibrosis and its transition to subsequent heart dysfunction. To study how TWEAK/FN14 pathway is integrated in RVH we analyzed FN14 KO mice after Pulmonary Artery Banding (PAB). We observed that FN14 is significantly upregulated in the right ventricle (RV) after PAB. FN14 KO mice at 3 weeks of PAB exhibited markedly decreased levels of cardiac fibrosis, which was clearly associated with reduced expression of profibrotic genes. The protective effect of FN14 ablation is connected with reduced proliferation of non-myocytes in RVs, confirming the positive input of FN14 activation on fibroblast proliferation in vitro. Further we observed that upon TWEAK stimulation the Col1A2 promoter in HEK293 cells is activated, and collagen synthesis in Rat2 fibroblasts is enhanced. TWEAK induced collagen synthesis was significantly reduced in FN14 KO heart fibroblasts as well as in Rat2 fibroblasts, treated with FN14 blocking antibody. Moreover, FN14 KO mice at 3 weeks of PAB exhibited decreased levels of prohypertrophic markers: ANP and beta-MHC. In addition, cardiomyocyte size was decreased suggesting that cardiomyocyte hypertrophy was reduced. Conversely, adFN14 overexpression resulted in a significant increase of cardiomyocyte size in vitro. Finally, RV function was markedly increased after banding in FN14 KO mice compared to wildtype littermates as demonstrated by MRI analysis. Taken together, our study suggests that FN14 might be a novel therapeutical target for the treatment of PAH.
- © 2011 by American Heart Association, Inc.