title: Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity.
abstract: Matrix metalloproteinase (MMP) activation contributes to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. Increased oxidative and nitrosative stress have been implicated in the activation of MMPs and also in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Thus, we hypothesized that MMP activation occurs in DOX-induced cardiotoxicity. Male Balb/c mice received a single injection of DOX (25 mg/kg i.p.) and were sacrificed 12 h, 1, 2, 3 and 4 days later. Hearts and aortae were harvested for MMP zymography. DOX induced time-dependent activation of MMPs both in the heart and in the aortic tissue with an earlier onset in the latter. These results demonstrate that MMP activation is an early event in DOX-induced cardiotoxicity and raises the possibility that MMP inhibitors may influence the outcome of this severe complication.
authors.affiliation: Inotek Pharmaceuticals Corporation, 100 Cummings Center, Suite #419E, Beverly, MA 01915, USA.
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015415:Biomarkers / Q000032:analysis; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000201:enzymology; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D015427:Reperfusion Injury / Q000139:chemically induced / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004317:Doxorubicin; D020782:Matrix Metalloproteinases