Myocardial matrix metalloproteinase-2: inside out and upside down

Abstract

Since their inaugural discovery in the early 1960s, matrix metalloproteinases (MMPs) have been shown to mediate multiple physiological and pathological processes. In addition to their canonical function in extracellular matrix (ECM) remodeling, research in the last decade has highlighted new MMP functions, including proteolysis of novel substrates beyond ECM proteins, MMP localization to subcellular organelles, and proteolysis of susceptible intracellular proteins in those subcellular compartments. This review will provide a comparison of the extracellular and intracellular roles of MMPs, illustrating that MMPs are far more interesting than the one-dimensional view originally taken. We focus on the roles of MMP-2 in cardiac injury and repair, as this is one of the most studied MMPs in the cardiovascular field. We will highlight how understanding all dimensions, such as localization of activity and timing of interventions, will increase the translational potential of research findings. Building upon old ideas and turning them inside out and upside down will help us to better understand how to move the MMP field forward.

Fibrosis and Fibrotic Gene Expression in Pediatric and Adult Patients With Idiopathic Dilated Cardiomyopathy

“…Interestingly, the ratio between MMP-2 and TIMP-2 in pediatric IDC patients did not significantly differ (NF = 1.05±0.30; IDC no fibrosis = 0.98±0.27; IDC with fibrosis = 0.90±0.32). Importantly, MMPs and TIMPs are known to impact intracellular targets as well as extracellular matrix (41–43). These intracellular targets cover many areas of cellular function including metabolism, cytoskeleton, transcription, translation, signal transduction, and apoptosis (41).…”

Polyphenols and Polypeptides in Chinese Rice Wine Inhibit Homocysteine-induced Proliferation and Migration of Vascular Smooth Muscle Cells

“…Among the MMPs, MMP-2 and MMP-9 are the major gelatinases that play an important role in the development of atherosclerosis by degradation of ECM. 24 Overexpression and activity of MMP-2 and MMP-9 could accelerate the development and rupture of atherosclerotic plaques. 25 In addition to their canonical function in ECM remodeling, researches in the last decade have highlighted new MMP-2 functions, including proteolysis of novel substrates beyond ECM proteins such as troponin I, 26 localization to subcellular organelles such as mitochondria, 27 and proteolysis of susceptible intracellular proteins in those subcellular compartments such as monocyte chemoattractant protein-3.…”

“…However, in atherosclerotic plaques, the expression and activity of MMP-2 and TIMP-2 are changed and result in undue degradation and synthesis of ECM. The activated MMP-2 can also activate other signaling pathways such as p-AKT and p-ERK1/2 that could induce the migration and proliferation of VSMCs, 24,29,30 and the degradation of ECM supplies space for the migration and proliferation of VSMCs. 13 What is more, the activated VSMCs can then secrete and activate more MMP-2 and aggravate the imbalance of MMP-2/TIMP-2, resulting in the development and rupture of atherosclerotic plaques.…”

Renoprotective effects of berberine through regulation of the MMPs/TIMPs system in streptozocin-induced diabetic nephropathy in rats

“…This, of course, results from the production of fibronectin (FN) and type IV collagen promoted by TGF-β1 (Ueno et al, 2013). Research has shown that the matrix metalloproteinases and tissue inhibitors of the matrix metalloproteinase (MMPs/TIMPs) system have non-neglectable roles in ECM accumulation and deposition (DeCoux et al, 2014;Raffetto and Khalil, 2008). Furthermore, the alterations in the MMPs and TIMPs are usually regulated by TGF-β (Kobayashi et al, 2014).…”