Carbon monoxide reduces the expression and activity of matrix metalloproteinases 1 and 2 in alveolar epithelial cells.
Matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-2, are involved in the pathophysiology of emphysema. MMPs contain zinc in the catalytic site and its expression is regulated transcriptionally via mitogen activated protein kinases (MAPKs). Carbon monoxide (CO), one of the end products of heme oxygenase activity, has anti-inflammatory properties, which are mediated, at least in part, by activation of p38 MAPK. Furthermore, CO has the unique ability to bind to metal centers in proteins and can affect their specific activity. Therefore, we hypothesized that CO could inhibit MMPs expression and/or activity. Here we show that a recently identified carbon monoxide-releasing molecule, [Ru(CO)3Cl2]2 (or CORM-2) inhibits MMP-1 and MMP-2 mRNA expression in the human lung epithelial cell line A549. The MMPs mRNA expression was unaffected by the p38 MAPK inhibitor SB203580, but in the case of MMP-1 was reversed by the antioxidant N-acetylcysteine. In addition, CORM-2 inhibited both MMP-1 and MMP-2 activities. Interestingly, no effect was observed with (Ru(DMSO)4Cl2), a negative control that does not contain CO groups. To the best of our knowledge this is the first evidence on the effect of CO on MMPs expression and activity. This effect could have important implications in the pathophysiology of emphysema and other diseases involving proteases/antiproteases imbalance.
Desmard
M
M
Institut National de la Santé et la Recherche Médicale (INSERM) Unité 700, and Institut Fédératif de Recherche 02, Faculté de Médecine Xavier Bichat, 75018 Paris, France.
Amara
N
N
Lanone
S
S
Motterlini
R
R
Boczkowski
J
J
D002248:Carbon Monoxide / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics
D053583:Interleukin-1beta; D009942:Organometallic Compounds; D012333:RNA, Messenger; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1