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Abstract
Free fatty acids (FFAs), elevated in metabolic syndrome and diabetes, play a crucial role in the development of atherosclerotic cardiovascular disease, and eicosapentaenoic acid (EPA) counteracts many aspects of FFA-induced vascular pathology. Although vascular calcification is invariably associated with atherosclerosis, the mechanisms involved are not completely elucidated. In this study, we tested the hypothesis that EPA prevents the osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC) induced by palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma. PA increased and EPA abolished the expression of the genes for bone-related proteins, including bone morphogenetic protein (BMP)-2, Msx2 and osteopontin in human aortic smooth muscle cells (HASMC). Among the long-chain acyl-CoA synthetase (ACSL) subfamily, ACSL3 expression was predominant in HASMC, and PA robustly increased and EPA efficiently inhibited ACSL3 expression. Importantly, PA-induced osteoblastic differentiation was mediated, at least in part, by ACSL3 activation because acyl-CoA synthetase (ACS) inhibitor or siRNA targeted to ACSL3 completely prevented the PA induction of both BMP-2 and Msx2. Conversely, adenovirus-mediated ACSL3 overexpression enhanced PA-induced BMP-2 and Msx2 expression. In addition, EPA, ACSL3 siRNA and ACS inhibitor attenuated calcium deposition and caspase activation induced by PA. Notably, PA induced activation of NF-κB, and NF-κB inhibitor prevented PA-induction of osteoblastic gene expression and calcium deposition. Immunohistochemistry revealed the prominent expression of ACSL3 in VSMC and macrophages in human non-calcifying and calcifying atherosclerotic plaques from the carotid arteries. These results identify ACSL3 and NF-κB as mediators of PA-induced osteoblastic differentiation and calcium deposition in VSMC and suggest that EPA prevents vascular calcification by inhibiting such a new molecular pathway elicited by PA.
Highlights
Vascular calcification commonly occurs with advancing age, chronic kidney disease, diabetes mellitus and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality [1,2,3]
palmitic acid (PA) Induces Osteoblastic Differentiation of vascular smooth muscle cells (VSMC) In a first step, we studied whether PA affected the expression of the genes coding for bone-related proteins in human aortic smooth muscle cells (HASMC), a primary culture of VSMC derived from human aorta, by measuring the mRNA levels by real-time PCR
These results suggest that a prevention of PA-induced osteoblastic differentiation by eicosapentaenoic acid (EPA) is associated with the inhibition of ACSL3 expression
Summary
Vascular calcification commonly occurs with advancing age, chronic kidney disease, diabetes mellitus and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality [1,2,3]. Accumulating evidence points toward an active and tightly regulated process that resembles bone mineralization, with phenotypic transition of vascular smooth muscle cells (VSMC). Osteoblastic differentiation and apoptosis, are involved in the development of vascular calcification [4]. Plasma concentrations of free fatty acids (FFAs) are increased in patients with metabolic syndrome [7], obesity [8] and type 2 diabetes mellitus [9]. Increasing evidence indicates that saturated FFAs activate inflammatory signaling pathways in vascular cells, including VSMC, macrophages and vascular endothelial cells. Miyazaki and his colleagues have provided evidence indicating that liver X receptor (LXR)-induced lipogenesis and saturated fatty acids stearic acid (SA) induce vascular calcification in vitro [11,12]
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