Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation.
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.
Chen
Chien-Lung
CL
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
Huang
Shoei K Stephen
SK
Lin
Jiunn-Lee
JL
Lai
Ling-Ping
LP
Lai
Shao-Chuan
SC
Liu
Chia-Wei
CW
Chen
Wen-Chi
WC
Wen
Cheng-Hao
CH
Lin
Chih-Sheng
CS
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
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9