SMAD2 and Myocardial fibrosis: In a mouse model of HFpEF (C57BL/6 mice with a high-fat diet and N-arginine methyl ester treatment), simvastatin reduced LVDD through a reduction of myocardial fibrosis, which was associated with the prevention of the phosphorylation of Smad (Smad2 and Smad3) and Ras/Raf/MAPK (mitogen-activated protein kinase) profibrotic signaling pathways downstream of the TGF-β receptor in cardiac tissue [127].