title: Cross-talk between NADPH oxidase-PKCα-p(38)MAPK and NF-κB-MT1MMP in activating proMMP-2 by ET-1 in pulmonary artery smooth muscle cells.
abstract: Treatment of bovine pulmonary artery smooth muscle cells with endothelin-1 (ET-1) caused an increase in the expression and activation of proMMP-2 in the cells. The present study was undertaken to determine the underlying mechanisms involved in this scenario. We demonstrated that (i) pretreatment with NADPH oxidase inhibitor, apocynin; PKC-α inhibitor, Go6976; p(38)MAPK inhibitor SB203580 and NF-κB inhibitor, Bay11-7082 inhibited the expression and activation of proMMP-2 induced by ET-1; (ii) ET-1 treatment to the cells stimulated NADPH oxidase and PKCα activity, p(38)MAPK phosphorylation as well as NF-κB activation by translocation of NF-κBp65 subunit from cytosol to the nucleus, and subsequently by increasing its DNA-binding activity; (iii) ET-1 increases MT1-MMP expression, which was inhibited upon pretreatment with apocynin, Go6976, SB293580, and Bay 11-7082; (iv) ET-1 treatment to the cells downregulated TIMP-2 level. Although apocynin and Go6976 pretreatment reversed ET-1 effect on TIMP-2 level, yet pretreatment of the cells with SB203580 and Bay 11-7082 did not show any discernible change in TIMP-2 level by ET-1. Overall, our results suggest that ET-1-induced activation of proMMP-2 is mediated via cross-talk between NADPH oxidase-PKCα-p(38)MAPK and NFκB-MT1MMP signaling pathways along with a marked decrease in TIMP-2 expression in the cells.
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India.
authors.forename: Jaganmay
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India.
authors.forename: Animesh
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India.
authors.forename: Tapati
authors.initials: T
authors.lastname: Chakraborti
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India. saj_chakra@rediffmail.com.
authors.forename: Sajal
authors.initials: S
authors.lastname: Chakraborti
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D018093:Gelatinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D004792:Enzyme Precursors; D016328:NF-kappa B; D019716:Tissue Inhibitor of Metalloproteinase-2; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D018093:Gelatinases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14
keywords: MT1-MMP; NADPH oxidase; NF-κB; PKC-α; TIMP-2; p38MAPK; proMMP-2