Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability

Abstract

The prevalence of atherosclerotic disease continues to increase, and despite significant reductions in major cardiovascular events with current medical interventions, an additional therapeutic window exists. Atherosclerotic plaque growth is a complex integration of cholesterol penetration, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) migration, and neovascular invasion. A family of matrix-degrading proteases, the matrix metalloproteinases (MMPs), contributes to all phases of vascular remodeling. The contribution of specific MMPs to endothelial cell integrity and VSMC migration in atherosclerotic lesion initiation and progression has been confirmed by the increased expression of these proteases in plasma and plaque specimens. Endogenous blockade of MMPs by the tissue inhibitors of metalloproteinases (TIMPs) may attenuate proteolysis in some regions, but the progression of matrix degeneration suggests that MMPs predominate in atherosclerotic plaque, precipitating vulnerability. Plaque neovascularization also contributes to instability and, coupling the known role of MMPs in angiogenesis to that of atherosclerotic plaque growth, interest in targeting MMPs to facilitate plaque stabilization continues to accumulate. This article aims to review the contributions of MMPs and TIMPs to atherosclerotic plaque expansion, neovascularization, and rupture vulnerability with an interest in promoting targeted therapies to improve plaque stabilization and decrease the risk of major cardiovascular events.

Matrix metalloproteinase collagenolysis in health and disease

“…Vascular smooth muscle cells use MT1-MMP to degrade and infiltrate three-dimensional collagenous barriers including the arterial wall (which is rich in type I collagen) [217]. Amongst several causes, atherosclerotic plaque vulnerability (rupture) has been postulated to result from processing of interstitial collagens in the fibrous cap of the plaque [218]. It is presently not clear which collagenase (MMP-1, MMP-8, and/or MMP-13) contributes to plaque instability [218].…”

“…Amongst several causes, atherosclerotic plaque vulnerability (rupture) has been postulated to result from processing of interstitial collagens in the fibrous cap of the plaque [218]. It is presently not clear which collagenase (MMP-1, MMP-8, and/or MMP-13) contributes to plaque instability [218]. …”

Immunohistochemical Characteristics of the Wall of Coronary Arteries in Experimental Atherosclerosis

“…На 16-му тижні експерименту в ІІ групі тварин 3 тип ДК змінював свою типову локалізацію в підендотеліальному шарі інтими і виявлявся поруч із внутрішньою еластичною мембраною, яка мала переривчастий контур, та в медії вінцевих артерій середнього калібру. Ймовірно, такі зміни стають можливими за рахунок продукції клітинами, залуче-ними в патологічний процес, матриксних металопротеїназ, які розщеплюючи компоненти екстрацелюлярного матриксу полегшують міграцію ДК [9]. Посилення міграційної активності відображалось в одночасному зростанні кількості 1 та 2 типу ДК (5,26±0,14 та 3,41±0,07 відповідно, р<0,05), в той час як вміст 3 типу ДК залишався на попередньому рівні.…”

Beneficial effect of successful simultaneous pancreas-kidney transplantation on plasma profile of metalloproteinases in type 1 diabetes mellitus patients

“…The matrix metalloproteinases (MMPs) family is a bundle of zinc-dependent proteases that are involved in the degradation and hydrolysis of extracellular matrix components [14]. Their activity contributes to all phases of vascular remodeling, especially in the diabetic and uremic milieu [14,15]. In T1D patients, some of MMPs were shown to be associated with arterial stiffness and pulse pressure [16], as well as cardiovascular events and all-cause mortality [17].…”