Activation of proMMP-2 by U46619 occurs via involvement of p(38)MAPK-NFκB-MT1MMP signaling pathway in pulmonary artery smooth muscle cells.
We investigated the mechanism by which TxA2 mimetic, U46619, activates proMMP-2 in bovine pulmonary artery smooth muscle cells. Our study showed that treatment of the cells with U46619 caused an increase in the expression and subsequently activation of proMMP-2 in the cells. Pretreatment with p(38)MAPK inhibitor, SB203580; and NF-κB inhibitor, Bay11-7082 inhibited the expression and activation of proMMP-2 induced by U46619. U46619 also induced increase in MT1-MMP expression, which was inhibited upon pretreatment with SB203580 and Bay11-7082. U46619 treatment to the cells stimulated p(38)MAPK activity as well as NF-κB activation by IκB-α phosphorylation, translocation of NF-κBp65 subunit from cytosol to nucleus and subsequently, by increasing its DNA-binding activity. Induction of NF-κB activation seems to be mediated through IKK, as transfection of cells with either IKKα or IKKβ siRNA prevented U46619-induced phosphorylation of IκB-α and NF-κBp65 DNA-binding activity. U46619 treatment to the cells also downregulated the TIMP-2 level. Pretreatment of the cells with SB203580 and Bay11-7082 did not show any discernible change in TIMP-2 level by U46619. Overall, U46619-induced activation of proMMP-2 is mediated via involvement of p(38)MAPK-NFκB-MT1MMP signaling pathway with concomitant downregulation of TIMP-2 expression in bovine pulmonary artery smooth muscle cells.
Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, 741235, West Bengal, India.
Animesh
A
Chowdhury
Soumitra
S
Roy
Tapati
T
Chakraborti
Kuntal
K
Dey
Sajal
S
Chakraborti
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004792:Enzyme Precursors; D020672:I-kappa B Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D019716:Tissue Inhibitor of Metalloproteinase-2; D000072000:NF-KappaB Inhibitor alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D018093:Gelatinases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14