Crucial Role of CD40 Signaling in Vascular Wall Cells in Neointimal Formation and Vascular Remodeling After Vascular Interventions

Song, Zifang; Jin, Rong; Yu, Shiyong; Nanda, Anil; Granger, D. Neil; Li, Guohong

doi:10.1161/atvbaha.111.238329

Cited by 37 publications

(52 citation statements)

References 58 publications

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“…37 In addition, both in vivo and in vitro data showed that TRAF6 deficiency prevented injury-induced SMC apoptosis but did not affect SMC proliferation and migration. 38 These findings suggest that TRAF6 might be a negative regulator of VSMC survival and vascular remodeling. However, another study found that TRAF6 silencing inhibited interleukin-1β-induced angiogenesis in mice in vivo, 39 implying a protective role of TRAF6 in vascular cell survival.…”

Section: Discussionmentioning

confidence: 92%

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

Dong

Song

et al. 2015

Circulation Research

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Recently, glucose metabolism has been highlighted as part of a novel mechanism involved in the complex regulation Molecular Medicine© 2015 American Heart Association, Inc. Objective: To identify the relationship between dihydronicotinamide adenine dinucleotide phosphate production and SM22α activity in the development and progression of vascular diseases. Methods and Results:We showed that the expression and activity of glucose-6-phosphate dehydrogenase (G6PD)are promoted in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. PDGF-BB induced G6PD membrane translocation and activation in an SM22α K21 ubiquitination-dependent manner. Specifically, the ubiquitinated SM22α interacted with G6PD and mediated G6PD membrane translocation. Furthermore, we found that tumor necrosis factor receptor-associated factor (TRAF) 6 mediated SM22α K21 ubiquitination in a K63-linked manner on PDGF-BB stimulation. Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, in parallel with reduced SM22α K21 ubiquitination. Elevated levels of activated G6PD consequent to PDGF-BB induction led to increased dihydronicotinamide adenine dinucleotide phosphate generation through stimulation of the pentose phosphate pathway, which enhanced VSMC viability and reduced apoptosis in vivo and in vitro via glutathione homeostasis. Conclusions:We provide evidence that TRAF6-induced SM22α ubiquitination maintains VSMC survival through increased G6PD activity and dihydronicotinamide adenine dinucleotide phosphate production. The TRAF6-SM22α-G6PD pathway is a novel mechanism underlying the association between glucose metabolism and VSMC survival, which is beneficial for vascular repair after injury but facilitates atherosclerotic plaque stability.

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Section: Discussionmentioning

confidence: 92%

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

Dong

Song

et al. 2015

Circulation Research

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“…Our laboratory has focused on investigating the role of CD40L/CD40 in the vascular response to injury. We have demonstrated that either antibody blockade of CD40L or genetic deletion of its receptor CD40 reduces early leukocyte (neutrophil and monocyte) accumulation in the injured arteries and limits eventual neointima formation after vascular injury in mice [16], [19], [32]. Nevertheless, the exact involvement of CD40L/CD40 in neutrophil recruitment and function remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…NF-kB p65 nuclear translocation in neutrophils was examined by immunocytochemical method, as previously described [19]. Briefly, freshly isolated neutrophils (from WT, CD40 −/− , and Mac-1 −/− mice) were resuspended in RPMI 1640 containing 0.5% (w/v) low-endotoxin BSA.…”

Section: Methodsmentioning

confidence: 99%

Soluble CD40 Ligand Stimulates CD40-Dependent Activation of the β2 Integrin Mac-1 and Protein Kinase C Zeda (PKCζ) in Neutrophils: Implications for Neutrophil-Platelet Interactions and Neutrophil Oxidative Burst

Jin

Song

et al. 2013

PLoS ONE

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Recent work has revealed an essential involvement of soluble CD40L (sCD40L) in inflammation and vascular disease. Activated platelets are the major source of sCD40L, which has been implicated in platelet and leukocyte activation, although its exact functional impact on leukocyte-platelet interactions and the underlying mechanisms remain undefined. We aimed to determine the impact and the mechanisms of sCD40L on neutrophils. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte recruitment to the sites of injury. Our data show that CD40L contributes to neutrophil firm adhesion to and transmigration across activated surface-adherent platelets, possibly through two potential mechanisms. One involves the direct interaction of ligand-receptor (CD40L-CD40), i.e., platelet surface CD40L interaction with neutrophil CD40; another involves an indirect mechanism, i.e. soluble CD40L stimulates activation of the leukocyte-specific β2 integrin Mac-1 in neutrophils and thereby further promotes neutrophil adhesion and migration. Activation of the integrin Mac-1 is known to be critical for mediating neutrophil adhesion and migration. sCD40L activated Mac-1 in neutrophils and enhanced neutrophil-platelet interactions in wild-type neutrophils, but failed to elicit such responses in CD40-deficient neutrophils. Furthermore, our data show that the protein kinase C zeta (PKCζ) is critically required for sCD40L-induced Mac-1 activation and neutrophil adhesive function. sCD40L strongly stimulated the focal clustering of Mac-1 (CD11b) and the colocalization of Mac-1 with PKCζ in wild-type neutrophils, but had minimal effect in CD40-deficient neutrophils. Blocking PKCζ completely inhibited sCD40L-induced neutrophil firm adhesion. Moreover, sCD40L strongly stimulates neutrophil oxidative burst via CD40-dependent activation of PI3K/NF-KB, but independent of Mac-1 and PKCζ. These findings may contribute to a better understanding of the underlying mechanisms by which sCD40L/CD40 pathway contributes to inflammation and vascular diseases.

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“…CD154 is expressed by a variety of immune and non-immune cells: apart from activated T-cells, activated platelets express CD154 at their surface and release soluble CD154 (sCD154); platelets represent a primary reservoir of CD154 and source of circulating sCD154 in the organism [Henn et al, 1998;Andre et al, 2002;Viallard et al, 2002]. CD154 may contribute to the regulation of matrix remodeling proteins, particularly through the induction of MMP-9 [Schonbeck et al, 1997;Mach et al, 1999;Li et al, 2008;Song et al, 2012;Bou Khzam et al, 2013].We hypothesized that the control of the production of matrix remodeling proteins by podocytes upon exposure to CD154 may contribute to GBM homeostasis. We therefore studied the expression of CD40 by podocytes and the involvement of CD40/ CD154 signalization in the regulation of MMP-9 expression in podocytes.…”

mentioning

confidence: 99%

CD154 Induces Matrix Metalloproteinase‐9 Secretion in Human Podocytes

Rigothier

Daculsi

Lepreux

et al. 2016

J of Cellular Biochemistry

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Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.

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Crucial Role of CD40 Signaling in Vascular Wall Cells in Neointimal Formation and Vascular Remodeling After Vascular Interventions

Cited by 37 publications

References 58 publications

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

Soluble CD40 Ligand Stimulates CD40-Dependent Activation of the β2 Integrin Mac-1 and Protein Kinase C Zeda (PKCζ) in Neutrophils: Implications for Neutrophil-Platelet Interactions and Neutrophil Oxidative Burst

CD154 Induces Matrix Metalloproteinase‐9 Secretion in Human Podocytes

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