RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Kassiri, Z  Oudit, GY  Sanchez, O  Dawood, F  Mohammed, FF  Nuttall, RK  Edwards, DR  Liu, PP  Backx, PH  Khokha, R 
Citation: Kassiri Z, etal., Circ Res. 2005 Aug 19;97(4):380-90. Epub 2005 Jul 21.
RGD ID: 1582576
Pubmed: PMID:16037568   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000178789.16929.cf   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Mmp13  (matrix metallopeptidase 13)
Mmp14  (matrix metallopeptidase 14)
Mmp2  (matrix metallopeptidase 2)

Genes (Mus musculus)
Mmp13  (matrix metallopeptidase 13)
Mmp14  (matrix metallopeptidase 14 (membrane-inserted))
Mmp2  (matrix metallopeptidase 2)

Genes (Homo sapiens)
MMP13  (matrix metallopeptidase 13)
MMP14  (matrix metallopeptidase 14)
MMP2  (matrix metallopeptidase 2)


Additional Information