Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity.
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.
Bai
Péter
P
Inotek Pharmaceuticals Corporation, 100 Cummings Center, Suite #419E, Beverly, MA 01915, USA.
Mabley
Jon G
JG
Liaudet
Lucas
L
Virág
László
L
Szabó
Csaba
C
Pacher
Pál
P
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
D000970:Antineoplastic Agents; D015415:Biomarkers; D004317:Doxorubicin; D020782:Matrix Metalloproteinases