Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease

Ungern‐Sternberg, Saskia N. I. von; Zernecke, Alma; Seizer, Peter

doi:10.3390/ijms19020507

Cited by 47 publications

(44 citation statements)

References 137 publications

(210 reference statements)

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“…The binding of CyPA to CD147 on the surface of platelets induces rapid degranulation and activation, leading to shape changes and the release of pro-inflammatory chemokines [4]. Furthermore, the CD147-CyPA interaction induces leukocyte chemotaxis and activation, expression of matrix-metalloproteinases, promotes atherosclerotic plaque formation, and plays critical roles in several inflammatory and cardiovascular diseases [14,[31][32][33]. CD147 has also been associated with other integrins, including α 3 β 1 and α 6 β 1 [2].…”

Section: Discussionmentioning

confidence: 99%

“…In the context of cardiovascular diseases, CyPA induces leukocyte chemotaxis and adhesion, and 2 of 9 myocardial MMP expression, facilitating subsequent myocardial remodeling. Inhibition of extracellular CyPA significantly decreases platelet activation and thrombus formation as well as the formation of monocyte-platelet aggregates [4,7,8,13,14]. Furthermore, our group identified glycoprotein VI (GPVI) to be an adhesion-mediating partner for CD147 on the platelet surface, which is the first time it has been demonstrated that CD147 plays a direct role in cell adhesive events, apart from mediating adhesion via intracellular signaling, leading to the expression of adhesion molecules [11].…”

Section: Introductionmentioning

confidence: 90%

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CD147 is a Novel Interaction Partner of Integrin αMβ2 Mediating Leukocyte and Platelet Adhesion

et al. 2020

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Surface receptor-mediated adhesion is a fundamental step in the recruitment of leukocytes and platelets, as well as platelet–leukocyte interactions. The surface receptor CD147 is crucially involved in host defense against self-derived and invading targets, as well as in thrombosis. In the current study, we describe the previously unknown interaction of CD147 with integrin αMβ2 (Mac-1) in this context. Using binding assays, we were able to show a stable interaction of CD147 with Mac-1 in vitro. Leukocytes from Mac-1−/− and CD147+/− mice showed a markedly reduced static adhesion to CD147- and Mac-1-coated surfaces, respectively, compared to wild-type mice. Similarly, we observed reduced rolling and adhesion of monocytes under flow conditions when cells were pre-treated with antibodies against Mac-1 or CD147. Additionally, as assessed by antibody inhibition experiments, CD147 mediated the dynamic adhesion of platelets to Mac-1-coated surfaces. The interaction of CD147 with Mac-1 is a previously undescribed mechanism facilitating the adhesion of leukocytes and platelets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

CD147 is a Novel Interaction Partner of Integrin αMβ2 Mediating Leukocyte and Platelet Adhesion

et al. 2020

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“…CD147 is a key player in the inflammation process [18,34,35]. Specific inhibition of CD147 with small interfering (si) RNA or monoclonal antibody (mAb) has been shown to exert profound anti-atherosclerotic effects, both in vitro and in vivo, through inhibition of CD147-mediated MMP-9 induction [34,36].…”

Section: Discussionmentioning

confidence: 99%

“…CD147-evoked promotion of the inflammation cascade occurs through interactions with several ligands, including CypA and intergrins [35]. Previous studies have shown that interactions of CD147 with CypA recruit inflammatory cells to inflamed tissue with upregulation of MMP production, and are closely associated with cardiovascular diseases [18,38].…”

Section: Discussionmentioning

confidence: 99%

SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice

Pahk

Joung

Song

et al. 2019

IJMS

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Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6, 6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.Keywords: atherosclerosis; plaque; plaque vulnerability; cluster of differentiation 147 (CD147); matrix metalloproteinase; matrix metalloproteinase-9 (MMP-9) Int.

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“…Of note, it was previously reported that EMMPRIN levels are strongly upregulated in VSMC of human non-syndromic TAA and its expression is induced in vitro by TGF-β and AngII [11][12][13]. Among EMMPRIN ligands important to be mentioned there are E-selectin, S100A9, and Cyclophilin A (CyPA) [14]. The latter is a peptidyl-prolyl cis-trans isomerase, object of several studies in the cardiovascular field [15,16].…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Perrucci

Rurali

Corlianò

et al. 2020

Cells

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Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.

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Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease

Cited by 47 publications

References 137 publications

CD147 is a Novel Interaction Partner of Integrin αMβ2 Mediating Leukocyte and Platelet Adhesion

CD147 is a Novel Interaction Partner of Integrin αMβ2 Mediating Leukocyte and Platelet Adhesion

SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice

Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

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