Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling.
The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-alpha receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively (P < 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 +/- 7.9%, 32.2 +/- 7.7%, and 21.6 +/- 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P < 0.04), and hypertrophy (heart weight-to-body weight ratios of 5.435 +/- 0.986, 5.485 +/- 0.677, and 6.726 +/- 0.704 mg/g, P < 0.04) were ameliorated in TNFR1KO mice. MMP-9 activity was highest at 3 days postinfarction and was highest in WT males (1.9 +/- 0.4 4, 3.6 +/- 0.24, 1.15 +/- 0.28, and 1.3 +/- 1.2 ng/100 microg protein, respectively, in TNFR1KO males, WT males, TNFR1KO females, and WT females, respectively, P < 0.002), whereas at 3 days TIMP-1 mRNA fold upregulation compared with type- and sex-matched controls was lowest in WT males (138.32 +/- 13.05, 46.74 +/- 5.43, 186.09 +/- 28.07, and 101.76 +/- 22.48, respectively, P < 0.002). MMP-2 and TIMP-2 increased similarly in all infarcted groups. These findings suggest that the benefits of TNFR1 ablation might be attributable at least in part to the attenuation of cytokine-mediated imbalances in MMP-TIMP activity.
Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Ravi
R
Ramani
Michael
M
Mathier
Ping
P
Wang
Gregory
G
Gibson
Sandra
S
Tögel
Jennifer
J
Dawson
Anthony
A
Bauer
Sean
S
Alber
Simon C
SC
Watkins
Charles F
CF
McTiernan
Arthur M
AM
Feldman
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017548:Echocardiography, Transesophageal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017379:Hypertrophy, Left Ventricular; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D010960:Plasminogen Activators / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D020257:Ventricular Remodeling
D015703:Antigens, CD; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019714:Tissue Inhibitor of Metalloproteinases; D019210:Troponin I; D010960:Plasminogen Activators; D020780:Matrix Metalloproteinase 9