Oct 12, 2011

Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress

Vijay KandalamZamaneh Kassiri


Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease. Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2(-/-)) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2(-/-)-TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin β1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2(-/-)-TAC hearts revealed degraded network structure as ...Continue Reading

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Mentioned in this Paper

Collagenase Activity
Stress, Mechanical
Left Ventricle Remodeling
Matrix Metalloproteinase 2 Measurement
Muscle Cells
Response to Biomechanical Stress
Extracellular Matrix
Ventricular Dysfunction, Left
Protein Phosphorylation

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