Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro

Hristov, Mihail; Erl, Wolfgang; Linder, Stefan; Weber, Peter

doi:10.1182/blood-2003-10-3614

Cited by 403 publications

(299 citation statements)

References 22 publications

(24 reference statements)

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“…SSC-apo and SSC-no-apo were centrifuged to eliminate cell debris and apoptotic bodies (28). Proteins in supernatants were concentrated, denatured, and digested with trypsin.…”

Section: Methodsmentioning

confidence: 99%

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

Cailhier

Sirois

Laplante

et al. 2008

Journal of Biological Chemistry

121

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Proteolysis of extracellular matrix components and the production of cryptic bioactive factors play key roles in vascular remodeling. We showed previously that extracellular matrix proteolysis is triggered by the apoptosis of endothelial cells (EC), resulting in the release of an anti-apoptotic C-terminal fragment of endorepellin (LG3). Here, we characterize the endorepellin-cleaving proteases released by apoptotic EC using a multifaceted proteomics strategy. Cathepsin L (CathL), a cysteine protease known to be associated with cardiovascular disease progression in animal models and humans, was isolated from medium conditioned by apoptotic EC. CathL cleaved recombinant endorepellin in vitro, leading to LG3 release. Inhibition of CathL activity in EC exposed to pro-apoptotic stimuli prevented LG3 release without modulating the development of apoptosis in EC. Inhibition of caspase-3 activation in EC with the biochemical inhibitor DEVD-fluoromethyl ketone or small interfering RNAs concomitantly prevented CathL release by EC, LG3 production, and the development of paracrine anti-apoptotic activity. These data demonstrate that caspase-3 activation is a novel pathway of importance for triggering extracellular CathL release and the cleavage of extracellular matrix components. Apoptosis of endothelial cells (EC)4 is increasingly recognized as an important component of the "response to injury" process, as most clinical risk factors of atherosclerosis (such as hypertension (1, 2), hyperglycemia (3, 4), oxidized low density lipoproteins (LDLs) (5, 6) and oxidative stress (7)) induce EC apoptosis. Interventions aimed at preventing EC apoptosis in animal models of transplant vasculopathy, an immune-mediated form of atherosclerosis, prevent neointima formation, indicating that EC apoptosis is an important pro-atherosclerotic trigger (8 -13). During vascular remodeling, EC injury and apoptosis are followed by migration of ␣-smooth muscle actinpositive cells (smooth muscle cells (SMC) and myofibroblasts) that accumulate within the intima through a state of resistance to apoptosis largely dependent on Bcl-xl overexpression (14 -16).Recent evidence from our group and others suggests that apoptotic EC favor neointima formation through the release of paracrine mediators, which in turn, increase Bcl-xl expression and inhibit the apoptosis of vascular SMC and fibroblasts (17)(18)(19)(20). The production of biologically active mediators by apoptotic EC is at least partially dependent on pericellular proteolysis, leading to basement membrane and extracellular matrix (ECM) degradation with the release of cryptic anti-apoptotic factors (18 -20). A C-terminal fragment of endorepellin (perlecan domain V) released in association with EC apoptosis was found to heighten Bcl-xl expression in SMC and fibroblasts (18 -20). Perlecan is a basement membrane modular proteoglycan composed of five structural domains (21). The C-terminal domain, also called endorepellin, comprises three laminin-like globular (LG1-LG3) modules interspaced by four epiderm...

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“…SSC-apo and SSC-no-apo were centrifuged to eliminate cell debris and apoptotic bodies (28). Proteins in supernatants were concentrated, denatured, and digested with trypsin.…”

Section: Methodsmentioning

confidence: 99%

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

Cailhier

Sirois

Laplante

et al. 2008

Journal of Biological Chemistry

121

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“…In contrast to exosomes (< 0.1 μm) that are released from intracellular compartments, platelet MPs are essentially vesicular fragments of platelet cytoplasm that are shed from the cytoplasmic membrane and express antigens from their parent cells at their surface, such as CD41 and CD62p (P-selectin); they can be distinguished from apoptotic bodies (> 1 μm) based on size [61]. Similar to exosomes and apoptotic bodies, MPs can exhibit phosphatidylserine, in consequence to the loss of membrane asymmetry that occurs during their release [62][63][64][65].…”

Section: Platelet Mpsmentioning

confidence: 99%

The clinical significance of platelet microparticle-associated microRNAs

Provost

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Abstract:Circulating blood platelets play a central role in the maintenance of hemostasis. They adhere to subendothelial extracellular matrix proteins that become exposed upon vessel wall damage, which is followed by platelet activation, further platelet recruitment, platelet aggregation and formation of an occlusive, or non-occlusive, platelet thrombus. Platelets host a surprisingly diverse transcriptome, which is comprised of ~ 9500 messenger RNAs (mRNAs) and different classes of non-coding RNAs, including microRNAs, as well as a significant repertoire of proteins that contribute to their primary (adhesion, aggregation, granule secretion) and alternative (RNA transfer, mRNA translation, immune regulation) functions. Platelets have the propensity to release microparticles (MPs; 0.1-1 μm in diameter) upon activation, which may mediate inflammatory responses and contribute to exacerbate inflammatory diseases and conditions. Carrying components of the platelets' cytoplasm, platelet MPs may exert their effects on recipient cells by transferring their content in platelet-derived bioactive lipid mediators, cytokines, mRNAs and microRNAs. Platelet MP-associated microRNAs may thus function also outside of platelets and play an important role in intercellular signaling and gene expression programming across the entire circulatory system. The role and importance of platelet MP-associated microRNAs in various aspects of biology and pathophysiology are increasingly recognized, and now provide the scientific basis and rationale to support further translational research and clinical studies. The clinical significance, pathophysiological role as well as the diagnostic and therapeutic potential of platelet MP-associated microRNAs in cardiovascular diseases, platelet transfusion and cancer will be discussed.

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“…[65][66][67][68][69] Apoptotic bodies from endothelial cells (larger than MPs) could also contribute to tissue repair mechanisms by stimulating the differentiation of progenitor cells. 70 …”

Section: Plasma Levels Of Mps In Cardiovascular Diseasesmentioning

confidence: 99%