Published online before print July 21, 2005, doi: 10.1161/01.RES.0000178789.16929.cf
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Submitted on April 18, 2005
Revised on July 12, 2005
Accepted on July 12, 2005
Combination of TNF
Ablation and MMP Inhibition Prevents Heart Failure After Pressure Overload in TIMP-3 Mutant Mice
Zamaneh Kassiri ;
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.
* To whom correspondence should be addressed. 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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