The Universal NF-kappaB Inhibitor A20 Protects From Transplant Vasculopathy by Differentially Affecting Apoptosis in Endothelial and Smooth Muscle Cells

Daniel, Soizic; Patel, Virendra I.; Shrikhande, Gautam; Scali, Salvatore T.; Ramsey, Haley E.; Csizmadia, Eva; Benhaga, Nordine; Fisher, Mark D.; Arvelo, Maria B.; Ferran, Christiane

doi:10.1016/j.transproceed.2006.10.167

Cited by 26 publications

(13 citation statements)

References 15 publications

(12 reference statements)

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“…This discrepancy highlights major cell‐type–specific differences in the function of the versatile A20 gene. This agrees with the opposite effects of A20 on cell proliferation in hepatocytes (pro‐proliferative by decreasing the expression of p21waf1) versus smooth muscle cells (antiproliferative by affecting the same target CDKI p21waf1, but in an opposite manner) 12, 31…”

Section: Discussionsupporting

confidence: 83%

A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-α expression

et al. 2009

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The nuclear factor-B inhibitory protein A20 demonstrates hepatoprotective abilities through combined antiapoptotic, antiinflammatory, and pro-proliferative functions. Accordingly, overexpression of A20 in the liver protects mice from toxic hepatitis and lethal radical hepatectomy, whereas A20 knockout mice die prematurely from unfettered liver inflammation. The effect of A20 on oxidative liver damage, as seen in ischemia/reperfusion injury (IRI), is unknown. In this work, we evaluated the effects of A20 upon IRI using a mouse model of total hepatic ischemia. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer. Although only 10%-25% of control mice injected with saline or the control rAd.␤ galactosidase survived IRI, the survival rate reached 67% in mice treated with rAd.A20. This significant survival advantage in rAd.A20-treated mice was associated with improved liver function, pathology, and repair potential. A20-treated mice had significantly lower bilirubin and aminotransferase levels, decreased hemorrhagic necrosis and steatosis, and increased hepatocyte proliferation. A20 protected against liver IRI by increasing hepatic expression of peroxisome proliferator-activated receptor alpha (PPAR␣), a regulator of lipid homeostasis and of oxidative damage. A20-mediated protection of hepatocytes from hypoxia/reoxygenation and H 2 O 2 -mediated necrosis was reverted by pretreatment with the PPAR␣ inhibitor MK886.In conclusion, we demonstrate that PPAR␣ is a novel target for A20 in hepatocytes, underscoring its novel protective effect against oxidative necrosis. By combining hepatocyte protection from necrosis and promotion of proliferation, A20-based therapies are well-poised to protect livers from IRI, especially in the context of small-for-size and steatotic liver grafts. Liver Ischemia/reperfusion injury (IRI) of the liver is a major cause of hepatic failure in the context of liver resection surgery, liver trauma, and liver transplantation.1,2 The clinical outcome of IRI is largely dependent on the severity of the insult and on the pre-existing condition of the liver. For instance, steatosis, which affects 25% of the western population, is a critical aggravating factor for IRI. 3The precise sequence of events leading to liver IRI has not been completely elucidated. There is, however, substantial evidence that ischemia depletes ATP levels (energy) and results in the activation of Kü pffer cells, production of proinflammatory cytokines such as tumor necrosis factor (TNF), generation of reactive oxygen species (ROS), and perturbation of the hepatic microcirculation. 4 These events lead to a massive inflammatory Abbreviations: ␤gal, ␤galactosidase; BrdU, 5 bromo-2-deoxyuridine; CDKI, cyclin-dependent kinase inhibitor; FA, fatty acids; HPF, high-power field; IRI, ischemia reperfusion injury; MOI, multiplicity of infection; NF-B, nuclear factor kappa B; PPAR␣, peroxisome proliferator-activated receptor alpha; rAd., recombinant adenovirus; ROS, reactive oxygen species; SEM, ...

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Section: Discussionsupporting

confidence: 83%

A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-α expression

et al. 2009

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“…1A). At 21 days post injury rats treated with rAd.βgal developed significant neointimal hyperplasia (Figure 1B&C), as previously reported,20 demonstrating that the myeloabaltive BMT protocol did not affect the response to balloon injury. In contrast, rats treated with rAd.A20 had negligible neointimal hyperplasia, with a significantly lower I/M ratio (n=5 per group; p=0.03).…”

Section: Resultssupporting

confidence: 86%

A20 inhibits post-angioplasty restenosis by blocking macrophage trafficking and decreasing adventitial neovascularization

et al. 2010

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OBJECTIVE-Neointimal hyperplasia is an inflammatory and proliferative process that occurs as a result of injury to the vessel wall. We have shown that the homeostatic protein A20 prevents neointimal hyperplasia by affecting endothelial cell (EC) and smooth muscle cell (SMC) responses to injury. In this work, we questioned whether A20 impacts other pathogenic effectors of neointimal hyperplasia including homing of monocyte/macrophages and EC/SMC precursors to the site of vascular injury, vascular endothelial growth factor (VEGF) secretion, and adventitial neovascularization.METHODS AND RESULTS-Carotid balloon angioplasty was performed on rat recipients of a bone marrow transplant from green fluorescent rats. Adenoviral delivery of A20 prevented neointimal hyperplasia and decreased macrophage infiltration. This was associated with decreased ICAM-1 and MCP-1 expression in vitro. Additionally, A20 reduced neovascularization in the adventitia of balloon injured carotid arteries, which correlated with fewer VEGF positive cells. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAtherosclerosis. Author manuscript; available in PMC 2011 August 1. CONCLUSIONS-A20 down-regulates adhesion markers, chemokine production, and adventitial angiogenesis, all of which are required for macrophage trafficking to sites of vascular injury. This, in turn, diminishes the inflammatory milieu to prevent neointimal hyperplasia.

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“…Several studies observed a correlation between A20 expression and prevention of graft atherosclerosis and chronic graft rejection [36,37]. In addition, adenovirus-mediated gene transfer of A20 reduced neointima formation after balloon angioplasty of rat carotid arteries, most likely by a dual effect on EC activation and smooth muscle cell proliferation and apoptosis [38,39]. Based upon these and other data, it was proposed that A20 gene transfer may have a beneficial effect on allograft survival [35].…”

Section: Discussionmentioning

confidence: 99%

Generation of Human Inflammation-Resistant Endothelial Progenitor Cells by A20 Gene Transfer

et al. 2009

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Inflammatory activation of the vascular endothelium is a major contributory factor to ischemic cardiovascular disease. Endothelial progenitor cells (EPCs) are being investigated for the treatment of ischemic disease or to coat vein grafts for bypass surgery. As an inflammatory environment might reduce their therapeutic efficacy, we sought to generate EPCs that are less sensitive to inflammatory activation. EPCs were obtained from human umbilical cord blood and transduced with a lentiviral vector for stable expression of A20, an anti-inflammatory protein. Nontransduced and green-fluorescent-protein-transduced cells were used as controls. Expression of A20 by EPCs did not modify cell morphology or expression of a panel of 20 proteins known to contribute to angiogenesis. Also, A20 had no effect on the capacity of EPCs to form tube-like structures in Matrigel™. A20 expression reduced EPC activation by tumor necrosis factor-α and interleukin-1β as determined from changes in vascular cell adhesion molecule 1 and E-selectin expression and decreased monocyte transmigration through a monolayer of EPCs. In conclusion, EPCs can be genetically modified to overexpress A20 in a stable fashion. These cells become less sensitive to inflammatory stimuli. This may be of interest in cell-based therapeutic approaches for clinical settings where inflammation is an important pathogenic factor.

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The Universal NF-kappaB Inhibitor A20 Protects From Transplant Vasculopathy by Differentially Affecting Apoptosis in Endothelial and Smooth Muscle Cells

Cited by 26 publications

References 15 publications

A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-α expression

A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-α expression

A20 inhibits post-angioplasty restenosis by blocking macrophage trafficking and decreasing adventitial neovascularization

Generation of Human Inflammation-Resistant Endothelial Progenitor Cells by A20 Gene Transfer

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