Extracellular Cyclophilin A Activates Platelets Via EMMPRIN (CD147) and PI3K/Akt Signaling, Which Promotes Platelet Adhesion and Thrombus Formation In Vitro and In Vivo

Seizer, Peter; Ungern‐Sternberg, Saskia N. I. von; Schönberger, Tanja; Münzer, Patrick; Schmidt, Eva-Maria; Mack, Andreas F.; Heinzmann, David; Chatterjee, Mainak; Langer, Harald F.; Malešević, Miroslav; Läng, Florian; Gawaz, Meinrad; Fischer, Günter; May, Andreas E.

doi:10.1161/atvbaha.114.305112

Cited by 81 publications

(77 citation statements)

References 35 publications

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“…150 Moreover, extracellular CyPA activates platelets via basigin (CD147)-mediated phosphoinositide-3-kinase/Akt signaling, leading to enhanced adhesion and thrombus formation. 151,152 Moreover, thrombin suppresses eNOS in EC via Rho-kinase pathway. 153 Thus, CyPA and Rho-kinase function in concert, leading to the development of vascular diseases.…”

Section: Rho-kinase-mediated Development Of Cardiovascular Diseasesmentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

370

235

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Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.

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Section: Rho-kinase-mediated Development Of Cardiovascular Diseasesmentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

370

235

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“…In this study we tested a cell-impermeable analog of CsA, MM284. MM284 is a CsA derivative that includes a negatively charged moiety coupled to presynthesized CsA (Malesevic et al, 2013;Seizer et al, 2015). The presence of this charged moiety prohibits passage of the compound through the plasma membrane, making it cell impermeable and capable of interacting with and inhibiting only extracellular pools of cyclophilins (Damsker et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…The presence of this charged moiety prohibits passage of the compound through the plasma membrane, making it cell impermeable and capable of interacting with and inhibiting only extracellular pools of cyclophilins (Damsker et al, 2009). This analog was compared with a cellpermeable analog of CsA, NIM811 (Rosenwirth et al, 1994;Seizer et al, 2015), which probably blocks activity of most mammalian cyclophilins (Arora et al, 2005). NIM811 was chosen as a control for MM284, because both analogs are nonimmunosuppressive.…”

Section: Resultsmentioning

confidence: 99%

“…Cyclophilins are expressed ubiquitously and participate in many intracellular inflammation-related pathways, including those relevant to the pathogenesis of atherosclerosis. For example, they stimulate expression of scavenger receptors (Nigro et al, 2011), activate platelets (Seizer et al, 2015), and regulate normal function of cholesterol transporter ATP-binding cassette transporter A1 (Le Goff et al, 2004). Additionally, cyclophilins are secreted both locally and into circulation; secreted extracellular cyclophilins also interfere with pathways relevant to atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

“…-CsA), a cell-impermeable cyclosporine derivative that only binds to extracellular cyclophilins (Malesevic et al, 2013;Seizer et al, 2015), and compared the effect of MM284 to the effect of NIM811 ([Melle] 4 -CsA), a cellpermeable nonimmunosuppressive cyclosporine A derivative, on development of atherosclerosis in an animal model of atherosclerosis. Surprisingly, while MM284 did exert antiinflammatory activity, it exacerbated atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Extracellular Cyclophilins with Cyclosporine Analog and Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Ditiatkovski

Neelisetti

Cui

et al. 2015

J Pharmacol Exp Ther

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Cyclophilins exert both intracellular and extracellular activities related to immune responses and inflammation, which have been implicated in pathogenesis of atherosclerosis. Pan-inhibition of cyclophilins has both pro-and antiatherosclerotic properties, but specific contributions of extracellular and intracellular cyclophilins to these effects have not been characterized. Here, using selective inhibitor of extracellular cyclophilins, we investigated the role of these molecules in atherosclerosis. Apolipoprotein E-null mice fed a high-fat diet received intraperitoneal injections every second day of either vehicle or two analogs of cyclosporine A (CsA): [Melle] 4 -CsA

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Nicht‐immunsuppressive Cyclophilin‐Inhibitoren

2022

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Cyclophiline, Enzyme mit einer Peptidyl-Prolyl-cis/trans-Isomerase-Aktivität, sind für eine Vielzahl biologischer Prozesse von Bedeutung. Das am häufigsten vorkommende Mitglied dieser Enzymfamilie, Cyclophilin A, ist der zelluläre Rezeptor des Immunsuppressivums Cyclosporin A (CsA). Aufgrund der pathophysiologischen Rolle der Cyclophiline, insbesondere bei Virusinfektionen, besteht ein breites Interesse an der Inhibierung von Cyclophilinen ohne immunsuppressive Wirkung. In diesem Überblick wird zunächst eine Einführung in die physiologische und pathophysiologische Rolle der Cyclophiline gegeben. Die Präsentation der nicht-immunsuppressiven Cyclophilin-Inhibitoren beginnt mit Wirkstoffen, die auf chemischen Modifikationen von CsA basieren. Die makrocyclischen, natürlich vorkommenden Sanglifehrine wurden zu einer weiteren Leitstruktur für Cyclophilin-inhibierende Wirkstoffe. Schließlich werden de novo entwickelte Verbindungen vorgestellt, deren Strukturen nicht von Naturstoffen abgeleitet oder durch sie inspiriert sind. Es werden relevante synthetische Konzepte erörtert, jedoch liegt auch ein Schwerpunkt auf biochemischen Untersuchungen, Struktur-Wirkungs-Beziehungen und klinischen Studien.

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Extracellular Cyclophilin A Activates Platelets Via EMMPRIN (CD147) and PI3K/Akt Signaling, Which Promotes Platelet Adhesion and Thrombus Formation In Vitro and In Vivo

Cited by 81 publications

References 35 publications

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Inhibition of Extracellular Cyclophilins with Cyclosporine Analog and Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Nicht‐immunsuppressive Cyclophilin‐Inhibitoren

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