SMAD2 and Myocardial fibrosis: In vivo and in vitro loss-of-function studies showed that VPO1 promoted cardiac fibroblast proliferation, migration and differentiation by catalyzing HClO formation, which further activated downstream Smad2/3.230 In a pressure overload model, Sirtuin 1 activation ameliorated cardiac fibrosis and hypertrophy by reducing the transcriptional activity of Smad2/3 by decreasing the acetylation level.231 In a myocardial fibrosis model induced by a combination of angiotensin II infusion and cardiac pressure overload, TIMP-1 exacerbated myocardial fibrosis in a metalloproteinase-independent manner.