Abstract
BackgroundSortilin, a member of the Vps10p-domain receptor family, has been demonstrated a key regulator in mediating cellular response to pro-neurotrophins. In the present study, we investigated the role of sortilin in the apoptotic pathway of vascular smooth muscle cells.Methods and Principal FindingsImmunohistochemistry revealed that sortilin was barely detectable in human and rat normal young vessels, while its expression was increased in human fibroatheromatous plaques. Sortilin immunodetection was also marked in the neointima of the rat aorta fifteen days after ballooning. In vitro, rat aortic intimal cells expressed higher sortilin levels than normal media SMCs; sortilin was distributed in the cytoplasm and in correspondence of the cell membrane. After 48 h, pro-nerve growth factor (proNGF) induced the strong dose-dependent increase of intimal cell apoptosis and the accumulation of sortilin protein. ProNGF was a more potent apoptotic inducer than equimolar or even higher concentration of NGF, whereas brain derived neutrotrophic factor was ineffective. Targeted interfering RNA-mediated sortilin reduction counteracted proNGF-induced apoptosis without affecting p75NTR expression. ProNGF-induced apoptosis was associated to NF-κB down-regulation and bax increase. Inhibition of NF-κB activity increased intimal cell apoptosis that did not further increase with the addition of proNGF.ConclusionsOur results indicate that sortilin expression characterizes human atheromatous lesions and rat aortic post-injury neointima, and suggest that sortilin represents an important regulator of proNGF-induced SMC apoptosis and arterial remodeling.
Highlights
Smooth muscle cell (SMC) accumulation within the intima characterizes human atheromatous plaque and restenosis following angioplasty or stenting procedures [1,2]
Our results indicate that sortilin expression characterizes human atheromatous lesions and rat aortic postinjury neointima, and suggest that sortilin represents an important regulator of pro-nerve growth factor (proNGF)-induced SMC apoptosis and arterial remodeling
In order to mediate such effect, p75 neurotrophin receptor (p75NTR) associates with sortilin, a member of the Vps10pdomain receptor family, expressed in embryonic as well as in adult tissues [22,23]. p75NTR has been detected in human atherosclerotic plaques and in rat aortic post-injury intimal thickening [24] and is implicated in SMC apoptosis [17]
Summary
Smooth muscle cell (SMC) accumulation within the intima characterizes human atheromatous plaque and restenosis following angioplasty or stenting procedures [1,2]. ProNGF has been shown to induce cell apoptosis through its binding to the p75 neurotrophin receptor (p75NTR) [20,22]. P75NTR has been detected in human atherosclerotic plaques and in rat aortic post-injury intimal thickening [24] and is implicated in SMC apoptosis [17]. Functionally associated with p75NTR, little information is available about sortilin distribution and its specific contribution to vascular remodeling, and in particular to SMC apoptosis. We demonstrated that sortilin intracellular redistribution and accumulation appear essential for proNGF-induced apoptosis of vascular SMCs, likely through the modulation of NF-kB activity. These findings support a relevant role of sortilin in post-injury arterial remodeling. We investigated the role of sortilin in the apoptotic pathway of vascular smooth muscle cells
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