Combination of tumor necrosis factor-α ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice

Kassiri, Zamaneh, Oudit, Gavin Y., Sanchez, Otto, Dawood, Fayez, Mohammed, Fazilat F., Nuttall, Robert K., Edwards, Dylan R. ORCID: https://orcid.org/0000-0002-3292-2064, Liu, Peter P., Backx, Peter H. and Khokha, Rama (2005) Combination of tumor necrosis factor-α ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circulation Research, 97. pp. 380-390.

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Abstract

show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3−/− mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNFα converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-α (TNFα) processing. In addition, TNFα production increased in timp-3−/−-AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3−/−-AB myocardium. Timp-3−/−/tnfα−/− mice were generated and subjected to AB for comparative analyses with timp-3−/−-AB mice. This revealed the critical role of TNFα in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFα, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFα, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3−/−-AB mice. Notably, combining TNFα ablation with MMP inhibition completely rescued heart disease in timp-3−/−-AB mice. This study provides a basis for anti-TNFα and MMP inhibitor combination therapy in heart disease.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Cells and Tissues Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Depositing User:	EPrints Services
Date Deposited:	01 Oct 2010 13:36
Last Modified:	03 Nov 2023 01:51
URI:	https://ueaeprints.uea.ac.uk/id/eprint/351
DOI:	10.1161/01.RES.0000178789.16929.cf

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