title: Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation.
abstract: Remodeling of atrial extracellular matrix (ECM) in atrial fibrillation (AF) involves changes in the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). The contributions of MMPs and TIMPs to the pathogenesis of AF development have not been clearly defined. This study evaluated the in situ activity and expression of gelatinases (MMP-2 and MMP-9) and their relationship with TIMP-1 or TIMP-3 in atria undergoing rapid atrial pacing for the induction of AF (4 weeks' pacing followed by 2 weeks of maintained AF) in pigs. In AF atria, in situ gelatinase activity was mainly localized in the interstitium of atrial myocardium, and was significantly larger than that of sinus rhythm control (i.e., sham control). The significant increase of MMP-9 in its pro-form and mRNA level, but not MMP-2, was shown to be responsible for the increased gelatinase activity in atria with AF. The inhibitory activities of glycosylated TIMP-1 and TIMP-3, but not TIMP-2, in AF tissues were markedly elevated and also localized in the atrial interstitium. TIMP-1 was found to be mostly colocalized with gelatinase activity over the AF tissues, implying the coexistence of gelatinase activity and TIMP-1, but TIMP-3 appeared only partially colocalized and discontinued the gelatinase activity surrounding the cardiomyocytes. TIMP-1 and TIMP-3 may play differential roles in the inhibition of gelatinase activity in vivo. Together with the survey of several MMPs transcripts and the level of transforming growth factor-beta1 (TGF-beta1), we proposed that the increased activity of gelatinase (i.e., MMP-9), TIMP-1 and TIMP-3 and their interaction may contribute to atrial ECM remodeling of AF.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chien-Lung
authors.initials: CL
authors.lastname: Chen
authors.forename: Shoei K Stephen
authors.initials: SK
authors.lastname: Huang
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.forename: Shao-Chuan
authors.initials: SC
authors.lastname: Lai
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liu
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chen
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Wen
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Lin
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D013552:Swine; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9