Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation

Abstract

Atherosclerotic plaque rupture provokes most myocardial infarctions. Matrix metalloproteinases (MMPs) have counteracting roles in intimal thickening, which stabilizes plaques, on the one hand and extracellular matrix destruction that leads to plaque rupture on the other. This review briefly summarizes the key points supporting the involvement of individual MMPs in provoking plaque rupture and discusses the barriers that stand in the way of clinical translation, which can be itemised as follows: structural and functional complexity of the MMP family; lack of adequate preclinical models partly owing to different expression patterns of MMPs and TIMPs in mouse and human macrophages; the need to target individual MMPs selectively; the difficulties in establishing causality in human studies; and the requirement for surrogate markers of efficacy. Overcoming these barriers would open the way to new treatments that could have a major impact on cardiovascular mortality worldwide.

Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol

“…In the circulation, neutrophils are considered to be the major source (Jönsson et al 2011, Newby 2015. The enzyme is stored in a latent form in gelatinase-rich (or tertiary) granules of neutrophils and rapidly released following stimulation (Soehnlein 2012).…”

Fatty Acid-Mediated Inhibition of Metal Binding to the Multi-Metal Site on Serum Albumin: Implications for Cardiovascular Disease

“…They degrade the extracellular matrix, cell surface components as well as intracellular proteins, and are therefore particularly important for vascular and cardiac tissue remodelling, both in normal conditions but also, e.g., during the development of atherosclerosis [127] and the adverse structural remodelling of the myocardium [128]. In atherosclerosis, they may either stabilise or promote rupture of plaques, and hence contribute to acute myocardial infarction [129]. Since they require a zinc cofactor, their activity may be modulated by zinc dyshomeostasis, although no detailed studies on this hypothesis are available.…”

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

“…Our recent studies demonstrated the predominant upregulation of MMP-12 and its pathological role in acute brain damage after ischemic stroke [4,5]. The temporal expression profile of various MMPs in ischemic rat brains after focal cerebral ischemia and reperfusion revealed that MMP-9 and MMP-12 were upregulated (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fold in case of MMP-9 and 47-265 fold in case of MMP-12 through days 1 to 7 after reperfusion) several fold higher than any other MMPs tested [4]. Evidence also suggests the detrimental role of MMP-9 and MMP-12 on post-stroke brain damage [4][5][6][7][8].…”