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Am J Physiol Heart Circ Physiol 287: H1369-H1377, 2004; doi:10.1152/ajpheart.00641.2003
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Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling

Ravi Ramani,1 Michael Mathier,1 Ping Wang,1 Gregory Gibson,1 Sandra Tögel,2 Jennifer Dawson,1 Anthony Bauer,2 Sean Alber,3 Simon C. Watkins,3 Charles F. McTiernan,1 and Arthur M. Feldman1

1Cardiovascular Institute, 2Division of Gastroenterology, and 3Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Submitted 16 July 2003 ; accepted in final form 6 April 2004

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 µg 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.

extracellular matrix; left ventricular function; myocardial infarction


Address for reprint requests and other correspondence: C. F. McTiernan, 1750 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213 (E-mail: mctiernanc{at}msx.upmc.edu).




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