Aim. Arterial smooth muscle cells (SMCs) may accumulate cholesterol and modify their phenotypic behavior becoming foam cells. We aimed to characterize the role of HDL3 and the ATP binding cassette transporter ABCA1 in this process. Methods. We evaluated the cholesterol-induced phenotypic changes in SMCs isolated from wild type (WT) and ABCA1 knock out (KO) mice and how HDL3 affects these changes. Results. Cholesterol loading downregulates the expression of ACTA2 (SMC-marker), and increases the expression of Mac-2, SRB1, ABCG1 and ABCA1 (macrophage-related genes). HDL3 normalizes ACTA2 expression and reduces the expression of macrophage-related genes in WT cells. Interestingly, the effect of HDL3 is completely lost in ABCA1 KO cells. Concordantly, ABCA1 knock-down by siRNA completely abolishes the rescue effect by HDL3 in WT SMC. The presence of HDL3 does not differently affect cholesterol accumulation in WT or ABCA1 KO cells and stimulates phospholipids removal only in WT cells. Cholesterol loading reduces the expression of myocardin, the key SMC transcriptional coactivator (-55%, p<0.01 vs control) in both cell types, while increases the expression of KLF4 (a transcriptional factor which represses the expression of myocardin) in WT cells (+240%, p<0.01 vs control). HDL3 normalizes myocardin and KLF4 levels in WT cells while it does not have any effect in ABCA1 KO cells. Similar results are obtained on miR-143/145, which positively regulate myocardin. Conclusions. HDL3 modulates the miR143/145-myocardin-KLF4 axis and prevents the cholesterol-induced phenotypic changes in SMC, but only in the presence of a functional ABCA1.
ABCA1 and HDL3 are required to modulate smooth muscle cells phenotypic switch after cholesterol loading / S. Castiglioni, M. Monti, A. Vettore, L. Arnaboldi, M. Canavesi, A. Corsini, S. Bellosta. - In: ATHEROSCLEROSIS. - ISSN 1879-1484. - 263(2017 Nov), pp. e64-e64. ((Intervento presentato al 85. convegno European Atherosclerosis Society Congress tenutosi a Prague (Czech Republic) nel 2017.
|Titolo:||ABCA1 and HDL3 are required to modulate smooth muscle cells phenotypic switch after cholesterol loading|
CASTIGLIONI, SILVIA (Primo)
CORSINI, ALBERTO (Penultimo)
BELLOSTA, STEFANO (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||nov-2017|
|Data ahead of print / Data di stampa:||ago-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.215|
|Appare nelle tipologie:||01 - Articolo su periodico|