Introduction: Increased oxidative stress and alteration of nitric oxide control have been involved in the cardiotoxicity of doxorubicin (DOX). A Disintegrin And Metalloproteinase (ADAMs) are transmembrane ectoproteases to regulate cell-cell and cell-matrix interactions, but their role in cardiac disease is unclear. The purpose of this study was to determine whether DOX activates peroxynitrite and ADAM and thus ADAM and matrix metalloproteinase (MMP) induce cardiac remodeling in DOX-induced cardiomyopathy. Methods and Results: Adult male Sprague-Dawley rats were subjected to cardiomyopathy by DOX (six equal injection, 2.5mg/kg DOX over a 2-week period), and were randomized four groups and followed by 3, 5, 7, and 14 days after cessation of DOX injection. DOX-injected animals significantly decreased left ventricular fractional shortening compared with control which were assessed by M-mode echocardiography. Morphometric analysis showed the increament of ventricular interstitial, nonvascular collagen deposition in DOX-heart, as determined by picrosirius red stains. The expressions of cardiac nitrotyrosine (a marker of peroxinitrite formation) by immunohistochemistry (IHC) were significant increased, and the higher rate of nitrotyrosine formation persisted for 2 weeks following the last injection. The expression of eNOS (IHC and western-blot) and iNOS (western-blot) were increased in DOX-heart compared with control. Compare to control rats, cardiac ADAM10 protein expression by western blot increased by 105 % at day 3, 123 % at day 5, 143 % at day 7, 177 % at day 14 after cessation of DOX injection (n= 10, each group). Active/total MMP2 proteolytic activity were increased by 130 % at day 14 in DOX-heart compared with control . Conclusions: These data suggest that activation of cardiac peroxynitrite and ADAM 10 - dependent MMP 2 may be a molecular mechanism that contributes to the left ventricular remodeling in DOX-induced cardiomyopathy.