A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia

Abstract

A20 is a NF-kappaB-dependent gene that has dual anti-inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti-inflammatory function via blockade of NF-kappaB and NF-kappaB-dependent proteins ICAM-1 and MCP-1. A20 inhibits SMC proliferation via increased expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine- and Fas-mediated apoptosis through a novel NO-dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re-endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti-inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease.

The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-κB target genes

“…One caveat of this conclusion is that our studies determining the relative activities of FVB-A20 and B6-A20 were done in transfected 293 and vascular smooth muscle cells, whereas in the current study A20 in lesions was localized mainly to endothelial cells and lipid-laden macrophages. Although unlikely, it is possible that A20 mediates different functions (antiapoptotic vs. NF-B activation) in these cell types so that in sum the FVB form could be proatherogenic (33,34). Thus it will be necessary to study cell type-specific conditional knockdown of A20 before entirely excluding it as the responsible atherosclerosis susceptibility gene at the chromosome 10 locus.…”

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

“…In SMC, NF-κB is essential for the acquisition of a pro-inflammatory SMC phenotype, promoting migration into the neointima, proliferation and leukocytes migration into TV lesions. Concommitant to NF-κB activation, A20 inhibits the subsequent up-regulation of proatherogenic NF-κB dependent genes such as ICAM-1 and MCP-1 and also A20 SMC proliferation via increased expression of the cyclin dependent kinase inhibitors p21 waf1 and p27 kip1 (12) . Further, we demonstrate that A20 expression in SMC results in sensitization to cytokine and Fas mediated apoptosis through a novel NO-dependent mechanism.…”

“…We have evidence that he 7Zn finger protein A20 is part of the protective phenotype of the vessel wall against TV. A20 is a NF-κB dependent stress response gene in EC and SMC with potent antiinflammatory effect in both cell types through blockade of NF-κB (11,12 ). However, its effect on apoptosis is rather cell type and stimulus specific.…”

Expression, biological activities and mechanisms of action of A20 (TNFAIP3)

“…In VSMCs transfected with A20, expression of p53 and the p53 target genes p21 waf1 and p27 kip is increased [85], which would be expected to contribute to the anti-proliferative effect of A20. The effect of A20-deficiency on cell proliferation has not yet been tested, which is essential to confirm that A20 regulates cell proliferation under physiological conditions.…”