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

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          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.

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          Most cited references 185

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          Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

           Z Galis,  P. Libby,  M Lark (1994)
          Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.
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            Trends in the leading causes of death in the United States, 1970-2002.

            The decrease in overall death rates in the United States may mask changes in death rates from specific conditions. To examine temporal trends in the age-standardized death rates and in the number of deaths from the 6 leading causes of death in the United States. Analyses of vital statistics data on mortality in the United States from 1970 to 2002. The age-standardized death rate and number of deaths (coded as underlying cause) from each of the 6 leading causes of death: heart disease, stroke, cancer, chronic obstructive pulmonary disease, accidents (ie, related to transportation [motor vehicle, other land vehicles, and water, air, and space] and not related to transportation [falls, fire, and accidental posioning]), and diabetes mellitus. The age-standardized death rate (per 100,000 per year) from all causes combined decreased from 1242 in 1970 to 845 in 2002. The largest percentage decreases were in death rates from stroke (63%), heart disease (52%), and accidents (41%). The largest absolute decreases in death rates were from heart disease (262 deaths per 100,000), stroke (96 deaths per 100,000), and accidents (26 deaths per 100,000).The death rate from all types of cancer combined increased between 1970 and 1990 and then decreased through 2002, yielding a net decline of 2.7%. In contrast, death rates doubled from chronic obstructive pulmonary disease over the entire time interval and increased by 45% for diabetes since 1987. Despite decreases in age-standardized death rates from 4 of the 6 leading causes of death, the absolute number of deaths from these conditions continues to increase, although these deaths occur at older ages. The absolute number of deaths and age at death continue to increase in the United States. These temporal trends have major implications for health care and health care costs in an aging population.
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              Tissue inhibitors of metalloproteinases: evolution, structure and function.

              The matrix metalloproteinases (MMPs) play a key role in the normal physiology of connective tissue during development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. An important mechanism for the regulation of the activity of MMPs is via binding to a family of homologous proteins referred to as the tissue inhibitors of metalloproteinases (TIMP-1 to TIMP-4). The two-domain TIMPs are of relatively small size, yet have been found to exhibit several biochemical and physiological/biological functions, including inhibition of active MMPs, proMMP activation, cell growth promotion, matrix binding, inhibition of angiogenesis and the induction of apoptosis. Mutations in TIMP-3 are the cause of Sorsby's fundus dystrophy in humans, a disease that results in early onset macular degeneration. This review highlights the evolution of TIMPs, the recently elucidated high-resolution structures of TIMPs and their complexes with metalloproteinases, and the results of mutational and other studies of structure-function relationships that have enhanced our understanding of the mechanism and specificity of the inhibition of MMPs by TIMPs. Several intriguing questions, such as the basis of the multiple biological functions of TIMPs, the kinetics of TIMP-MMP interactions and the differences in binding in some TIMP-metalloproteinase pairs are discussed which, though not fully resolved, serve to illustrate the kind of issues that are important for a full understanding of the interactions between families of molecules.
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                Author and article information

                Journal
                9206092
                1126
                J Vasc Res
                J. Vasc. Res.
                Journal of vascular research
                1018-1172
                1423-0135
                4 April 2020
                22 June 2016
                2016
                04 May 2020
                : 53
                : 1-2
                : 1-16
                Affiliations
                [a ]Division of Vascular Surgery, Department of Surgery, Medical University of South Carolina, Charleston, S.C., USA
                [b ]Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, S.C., USA
                [c ]Division of Cardiothoracic Research, Department of Surgery, Medical University of South Carolina, Charleston, S.C., USA
                Author notes
                Dr. Jean Marie Ruddy, Division of Vascular Surgery, Department of Surgery, Medical University of South Carolina, 114 Doughty Street, MSC 295, Charleston, SC 29425 (USA), ruddy@ 123456musc.edu
                Article
                NIHMS1581482
                10.1159/000446703
                7196926
                27327039

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. http://creativecommons.org/licenses/by-nc-nd/4.0/

                Categories
                Article

                Cardiovascular Medicine

                angiogenesis, atherosclerosis, plaque rupture, matrix metalloproteinases

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