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(Circulation Research. 2005;97:380.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Combination of Tumor Necrosis Factor- Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice

Zamaneh Kassiri, Gavin Y. Oudit, Otto Sanchez, Fayez Dawood, Fazilat F. Mohammed, Robert K. Nuttall, Dylan R. Edwards, Peter P. Liu, Peter H. Backx, Rama Khokha

From the Ontario Cancer Institute (Z.K., O.S., F.F.M., R.K.), University of Toronto, University Health Network, Canada; Heart and Stroke/Richard Lewar Center of Excellence (G.Y.O., F.D., P.P.L., P.H.B.), University of Toronto, Ontario, Canada; and the School of Biological Sciences (R.K.N., D.R.E.), University of East Anglia, Norwich, Norfolk, United Kingdom.

Correspondence to Rama Khokha, Ontario Cancer Institute, University of Toronto, 610 University Ave, 10–330, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada. E-mail rkhokha{at}uhnres.utoronto.ca

Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we 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 TNF converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor- (TNF) processing. In addition, TNF 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^–/–/tnf^–/– mice were generated and subjected to AB for comparative analyses with timp-3^–/–-AB mice. This revealed the critical role of TNF in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF, 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 TNF ablation with MMP inhibition completely rescued heart disease in timp-3^–/–-AB mice. This study provides a basis for anti-TNF and MMP inhibitor combination therapy in heart disease.

Key Words: left ventricular dilation and dysfunction • extracellular matrix • tissue inhibitor of metalloproteinase-3 • matrix metalloproteinase • tumor necrosis factor-

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