Tissue inhibitor of metalloproteinases-4 suppresses vascular smooth muscle cell migration and induces cell apoptosis

Guo, Yanhong; Gao, Wei; Li, Qian; Li, Pengfei; Yao, Peng-Ying; Chen, Kuang‐Hueih

doi:10.1016/j.lfs.2004.07.007

Cited by 55 publications

(43 citation statements)

References 24 publications

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“…To further categorize the effect of MMPs on migration, we used recombinant TIMPs, all of which reduced migration, TIMP-4 being the most potent. TIMP-4 strongly binds MMP-2 (2) and reduces vascular smooth muscle migration to a similar degree as we have observed in ASM (17). In keeping with our other findings, thrombin, a known activator of MMP-2, dosedependently enhanced ASM migration.…”

Section: Discussionsupporting

confidence: 91%

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Henderson¹,

Markwick²,

Elshaw³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Henderson N, Markwick LJ, Elshaw SR, Freyer AM, Knox AJ, Johnson SR. Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration. Am J Physiol Lung Cell Mol Physiol 292: L1030-L1038, 2007. First published December 22, 2006; doi:10.1152/ajplung.00317.2006.-Increased proinflammatory mediators and ECM deposition are key features of the airways in asthma. Matrix metalloproteinases (MMPs) are produced by airway smooth muscle (ASM) cells and have multiple roles in inflammation and tissue remodeling. We hypothesized that components of the asthmatic airway would stimulate MMP production and activation by ASM and contribute to airway remodeling. We measured human ASM-derived MMP mRNA, protein, and activity by real-time RT-PCR, zymography, Western blotting, and MMP activity assay. Collagen I and thrombin caused a synergistic increase in MMP-2 protein and total MMP activity but paradoxically decreased MMP-2 mRNA. Additionally, collagen I activated MMP-2 in culture supernatants independent of the cell surface. Together, collagen I and thrombin strongly enhanced MMP-14 mRNA and protein but had no effect individually, suggesting increased MMP-14, the activating protease for MMP-2, may be partially responsible for MMP-2 activation. Furthermore, collagen I reduced tissue inhibitor of metalloproteinase-2 protein (TIMP-2). We examined the role of MMPs in functions of ASM related to airway remodeling and found migration and proliferation were MMP dependent, whereas adhesion and apoptosis were not. Ilomastat inhibited migration by 25%, which was also inhibited by TIMPs 1-4 and increased by the MMP-2 activator thrombin. These in vitro findings suggest that the environment within the airways of patients with asthma enhances MMP-2 and -14 protein and activity by a complex interaction of transcriptional and posttranscriptional mechanisms, which may contribute to ASM migration. matrix metalloproteinases; asthma PATIENTS WITH ASTHMA DEVELOP structural airway changes termed remodeling. Starting in infancy, remodeling is categorized by airway smooth muscle (ASM) hypertrophy, hyperplasia, increased subepithelial myofibroblasts, altered ECM deposition, infiltration of ASM by mast cells, increased mucosal vascularity, epithelial shedding, metaplasia, and mucus gland hyperplasia (1,22,43). Remodeling results in bronchial hyperresponsiveness and airflow obstruction and, therefore, increased symptoms and use of asthma medication and health care resources (1, 34). The ASM cell is emerging as a key cell in airway remodeling being increased in both size and number in the airways of patients with asthma (4). Moreover, ASM cells produce ECM components (10), pro-and anti-inflammatory mediators, and growth factors of relevance to airway remodeling, including vascular endothelial growth factor (30), interleukin-8 (52), eotaxin (41), and prostaglandin E 2 (39). Thus the ASM cell is an important modulator of inflammation, inflammatory cell influx, and angiogenesis in the asthmatic ...

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Section: Discussionsupporting

confidence: 91%

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Henderson¹,

Markwick²,

Elshaw³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In contrast, the lower LV volumes in the TIMP-4OE mice with LVPO would reduce this mechanical stimulus and hence compensatory myocardial growth. Second, different TIMPs affect cell growth and viability in unique ways (5,7,13,19,21), and the present study identified that modifying TIMP-4 expression in turn affected expression of other TIMPs. For example, a marked increase in TIMP-1 expression was observed following LVPO in the TIMP-4KO mice, whereby TIMP-1 has been shown to accelerate growth in several cell lines and systems as well as inhibit apoptosis (5,7,19,30).…”

Section: Differential Effects Of Timp-4 On Survival and Function Withmentioning

confidence: 52%

“…However, the four known mammalian TIMPs, which are the products of distinct genes with very different sequences, are likely to display unique functionality beyond MMP inhibition (5, 6). For example, comparative studies in vitro have identified that TIMP-4 can affect fibro- blast transdifferentiation and vascular smooth muscle cell apoptosis independent of MMP inhibitory effects (13,19). However, much less is known about the in vivo effects of TIMP-4 in terms of a pathological stimulus, such as LVPO.…”

Section: Discussionmentioning

confidence: 99%

Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

Yarbrough

Baicu

Mukherjee

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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MR, Spinale FG. Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 307: H752-H761, 2014. First published July 3, 2014; doi:10.1152/ajpheart.00063.2014.-Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 Ϯ 0.1 mo of age, equal sex distribution) with TIMP-4OE (n ϭ 38), TIMP-4KO (n ϭ 24), as well as age/strain-matched wild type (WT, n ϭ 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ϳ25% lower in the TIMP-4KO group (P Ͻ 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 Ϯ 2% and 45 Ϯ 3%, respectively) but was higher with TIMP-4OE (57 Ϯ 2%, P Ͻ 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups (P Ͻ 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.remodeling; tissue inhibitors of metalloproteinase; pressure-overload hypertrophy LEFT VENTRICULAR (LV) pressure overload (LVPO), which occurs secondary to aortic valve stenosis and/or systemic hypertension, causes myocyte hypertrophy and abnormal extracellular matrix (ECM) accumulation. While both of these cellular and extracellular processes represent crucial events in the progression of LVPO, past studies have demonstrated that the progressive changes in both the content and structure of the ECM secondary to LVPO directly affect LV function and clinical outcomes (2,3,8,18,22,31). One pathway that contributes to ECM content and turnover is the expression and activation of the matrix metalloproteinases (MMPs), and the relationship to the endogenous tissue inhibitors of MMPs (TIMPs) (5-7, 27). TIMPs were initially identified to bind to active MMPs, and hence these small-molecular-weight proteins w...

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“…Targeted overexpression of TIMP-3 in macrophages effectively reduced plaque size and inflammatory infiltrate while promoting plaque stabilization through increased intact collagen, supporting TIMP-3 as a key mediator of proteolytic activity [179]. Adenovirus-mediated overexpression of TIMP-4 in carotid and aortic VSMCs effectively inhibited MMP-2 activation and VSMC migration while inducing apoptosis in these cells [180], but appropriate application of this data to atherosclerotic plaque stability requires further investigation. The safe and effective delivery of these adenoviruses to atherosclerotic plaques poses a significant challenge, but investigation into utilization of genetic variants has been initiated [181].…”

Section: Targets To Promote Plaque Stabilizationmentioning

confidence: 99%

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

Ruddy¹,

Ikonomidis²,

Jones³

2016

J Vasc Res

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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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Tissue inhibitor of metalloproteinases-4 suppresses vascular smooth muscle cell migration and induces cell apoptosis

Cited by 55 publications

References 24 publications

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

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

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