TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction.
The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3(-/-)). The coronary artery was ligated in timp-3(-/-) and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure-volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3(-/-) than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3(-/-) mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-alpha levels were significantly greater in timp-3(-/-) than in WT mice at different times after ligation. By histological evaluation, timp-3(-/-) mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium.
Tian
Hai
H
Division of Cardiovascular Surgery, Toronto General Research Institute, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada.
Cimini
Massimo
M
Fedak
Paul W M
PW
Altamentova
Svetlana
S
Fazel
Shafie
S
Huang
Ming-Li
ML
Weisel
Richard D
RD
Li
Ren-Ke
RK
D000818:Animals; D017209:Apoptosis; D001808:Blood Vessels / Q000201:enzymology / Q000473:pathology; D002306:Cardiac Volume; D049109:Cell Proliferation; D004452:Echocardiography; D024022:Fibrillar Collagens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011312:Pressure; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000502:physiology*
D024022:Fibrillar Collagens; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2