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Tissue inhibitor of metalloproteinases (TIMPs) in heart failure

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Abstract

Remodeling of the myocardium and the extracellular matrix (ECM) occurs in heart failure irrespective of its initial cause. The ECM serves as a scaffold to provide structural support as well as housing a number of cytokines and growth factors. Hence, disruption of the ECM will result in structural instability as well as activation of a number of signaling pathways that could lead to fibrosis, hypertrophy, and apoptosis. The ECM is a dynamic entity that undergoes constant turnover, and the integrity of its network structure is maintained by a balance in the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). In heart disease, levels of MMPs and TIMPs are altered resulting in an imbalance between these two families of proteins. In this review, we will discuss the structure, function, and regulation of TIMPs, their MMP-independent functions, and their role in heart failure. We will review the knowledge that we have gained from clinical studies and animal models on the contribution of TIMPs in the development and progression of heart disease. We will further discuss how ECM molecules and regulatory genes can be used as biomarkers of disease in heart failure patients.

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Abbreviations

ADAM:

A disintegrin and matrix metalloproteinase

CITP:

Carboxy-terminal telopeptide of collagen type I

DCM:

Dilated cardiomyopathy

ECM:

Extracellular Matrix

FGF:

Fibroblast growth factor

HB-EGF:

Heparin-bound epidermal growth factor

IL:

Interleukin

LV:

Left ventricle

MI:

Myocardial infarction

MMP:

Matrix metalloproteinase

MT-MMP:

Membrane-type MMP

PDGF:

Platelet-derived growth factor

PICP:

Procollagen type I carboxy-terminal propeptide

PINP:

Procollagen type I amino-terminal propeptides

PIIINP:

Procollagen type III amino-terminal pro-peptide

TIMP:

Tissue inhibitor metalloproteinase

TGFβ:

Transforming growth factor-beta

TNFα:

Tumor necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

WT:

Wild-type

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Acknowledgments

ZK is a New Investigator of Heart and Stroke Foundation of Canada (HSFC) and an Alberta Innovates-Health Solutions (AIHS) Scholar. VK is supported by AIHS studentship, and RB is supported by Motyl Scholarship.

Conflict of interest

L. Moore, V. Kandalam, and Drs. Fan, Basu, and Kassiri have no conflicts of interest or financial ties to disclose.

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Authors and Affiliations

  1. Department of Physiology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Rm 474, Heritage Medical Research Centre, Edmonton, AB, T6G 2S2, Canada

    Linn Moore, Dong Fan, Ratnadeep Basu, Vijay Kandalam & Zamaneh Kassiri

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  1. Linn Moore
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  2. Dong Fan
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  3. Ratnadeep Basu
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Correspondence to Zamaneh Kassiri.

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Moore, L., Fan, D., Basu, R. et al. Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail Rev 17, 693–706 (2012). https://doi.org/10.1007/s10741-011-9266-y

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