Tissue inhibitor of metalloproteinases (TIMPs) in heart failure

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.

Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

“…Enhanced MMP2 Activation in Timp3 Ϫ/Ϫ Mice following 2 Weeks of Angiotensin II Infusion-TIMP3 is a potent inhibitor of a number of active MMPs and can inhibit cell surface activation of MMP2 (33); hence, its absence can lead to uncontrolled proteolytic activities (34). In situ gelatin zymography showed that Ang II infusion resulted in a stronger gelatinase activity in Timp3 Ϫ/Ϫ compared with WT aorta ( Fig.…”

Cardiac remodelling: General aspects and mechanisms

“…CFBs also produce matrix metalloproteinases (MMPs) as well as tissue inhibitors of MMPs (TIMPs), which are ECM-regulatory proteins. MMPs are proteases that degrade ECM proteins and TIMPs can inhibit MMP function; their balanced equilibrium is critical for ECM homeostasis (59). Fibrosis is a response of hyperactivity of CFBs that proliferates in response to certain stressful stimuli, and recruitment and proliferation of circulating bone marrow-derived cells that infiltrate the myocardium and transform into CFBs (60).…”

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

“…Function of MMPs is balanced by their inhibitors, tissue inhibitor of metalloproteinase (TIMPs) to achieve optimal ECM composition [24]. Impairment of this delicate balance is fundamental to the pathogenesis of aortic aneurysm formation, expansion and rupture [5,15,[25][26][27][28].…”

“…AAA = abdominal aortic aneurysm; ApoE = apolipoprotein E; CaCl 2 =calcium chloride; MCP-4 = mast cell protein-4; MMP = matrix metalloproteinase; plg = plasminogen; TAA = thoracic aortic aneurysm; TIMP = tissue inhibitor of matrix metalloproteinase. ranging from 21-30 kDa that serve as potent endogenous inhibitors of MMPs through a covalent bond between their N-terminus and the catalytic domain in the activated MMPs [24]. All four TIMPs (TIMP1-4) are found in vertebrates and their expression levels are modulated during tissue remodelling or development [29].…”

“…All four TIMPs (TIMP1-4) are found in vertebrates and their expression levels are modulated during tissue remodelling or development [29]. TIMP3 is unique as it is the only TIMP bound to the ECM via its C terminal domain that provides extra reservoir by prolonging its half life [30] and has a broad inhibitory substrate profile which includes a number of disintegrin and metalloproteinase (ADAMs) [24,31].…”