title: Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice.
abstract: 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 TNFalpha converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-alpha (TNFalpha) processing. In addition, TNFalpha 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(-/-)/tnfalpha(-/-) mice were generated and subjected to AB for comparative analyses with timp-3(-/-)-AB mice. This revealed the critical role of TNFalpha in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFalpha, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFalpha, 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 TNFalpha ablation with MMP inhibition completely rescued heart disease in timp-3(-/-)-AB mice. This study provides a basis for anti-TNFalpha and MMP inhibitor combination therapy in heart disease.
authors.affiliation: Ontario Cancer Institute, University of Toronto, University Health Network, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Otto
authors.initials: O
authors.lastname: Sanchez
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.forename: Fazilat F
authors.initials: FF
authors.lastname: Mohammed
authors.forename: Robert K
authors.initials: RK
authors.lastname: Nuttall
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology; D006333:Heart Failure / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D020784:Matrix Metalloproteinase 8 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000627:therapeutic use*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D020784:Matrix Metalloproteinase 8; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse