MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodeling.

Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin. Doxorubicin enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against doxorubicin cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodeling the extracellular matrix.8-week old male C57BL/6J mice were treated with doxorubicin weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodeling before and after treatment. MMP inhibitors ameliorated doxorubicin-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodeling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. Doxorubicin increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that doxorubicin elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. Doxorubicin-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. Doxorubicin also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.MMP-2 activation is an early event in doxorubicin cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated doxorubicin cardiotoxicity by attenuating intracellular and extracellular matrix remodeling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.Heart failure is the primary chronic toxicity of anthracycline chemotherapy. Anthracyclines such as doxorubicin cause left ventricular remodeling and loss of myofilament proteins. We determined in mice whether matrix metalloproteinase-2, an intracellular and extracellular protease in the heart, contributes to doxorubicin cardiotoxicity. Doxorubicin activated myocardial MMP-2 in mouse hearts and human cardiomyocytes, including de novo expression of an N-terminal truncated MMP-2 isoform which is exclusively expressed by increased oxidative stress. Increased MMP-2 levels and activity in the heart contributed to left ventricular remodeling, interstitial fibrosis, and titin proteolysis in doxorubicin cardiotoxicity. These adverse effects on the heart were prevented by two orally available MMP inhibitors, demonstrating the potential benefits of MMP inhibition in the prophylaxis of doxorubicin cardiotoxicity.