Matrix metalloproteinase-9/tissue inhibitors of metalloproteinase-1 expression and atrial structural remodeling in a dog model of atrial fibrillation: inhibition with angiotensin-converting enzyme.
BACKGROUND
Matrix metalloproteinases and tissue inhibitors of metalloproteinases regulate extracellular matrix turnover in cardiac tissues. However, alteration of matrix metalloproteinases and tissue inhibitors of metalloproteinases during atrial fibrillation is unclear. This study aims to determine (a) the relationship between altered expressions of matrix metalloproteinases and tissue inhibitors of metalloproteinases and atrial structural remodeling; (b) the role of changes in the atrial angiotensin system and in calcium concentration; and (c) the effect of captopril on the expressions of matrix metalloproteinase-9/tissue inhibitors of metalloproteinase-1 and atrial structural remodeling.


METHODS
In left atrial tissue samples, the mRNA expression of angiotensin-converting enzyme, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1; the protein expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1; and Ca(2+) concentration and angiotensin II were measured.


RESULTS
Compared with controls, dogs under atrial fibrillation showed significantly increased contents of Ca(2+), angiotensin II , and interstitial fibrous tissue (P<.05-.001). The mRNA levels of angiotensin-converting enzyme, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 were significantly increased as compared with controls (P<.05-.01). The protein level of matrix metalloproteinase-9 was higher, and that of tissue inhibitors of metalloproteinase-1 was lower, in dogs with atrial fibrillation than in controls (P<.01-.001). All findings highlighted above were reversed by treatment with captopril.


CONCLUSIONS
Altered expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 contributes to atrial extracellular matrix remodeling and atrial dilatation. Angiotensin-II-mediated intracellular Ca(2+) overload may be the mechanism of altered expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1. Angiotensin-converting enzyme inhibitor treatment may attenuate atrial structural remodeling by normalizing the balance between matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1.
Zhang
Wei
W
Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan 250012, PR China.
Zhong
Ming
M
Yang
Gui-rong
GR
Li
Jian-ping
JP
Guo
Chenhong
C
Wang
Zhihao
Z
Zhang
Yun
Y
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D004285:Dogs; D015870:Gene Expression; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D020780:Matrix Metalloproteinase 9; D002118:Calcium