Docosahexaenoic acid-induced unfolded protein response, cell cycle arrest, and apoptosis in vascular smooth muscle cells are triggered by Ca²⁺-dependent induction of oxidative stress

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• 作者：Slaven Crnkovic^a ; ^b ; Monika Riederer^a ; Margarete Lechleitner^a ; Seth Hallströ ; m^c ; Roland Malli^a ; Wolfgang F. Graier^a ; Jö ; rg Lindenmann^d ; Helmut Popper^e ; Horst Olschewski^f ; Andrea Olschewski^b ; Sa&scaron ; a Frank^a ; ^{sasa.frank@medunigraz.at}
• 关键词：ATF6 ; activating transcription factor 6 ; DHA ; docosahexaenoic acid ; 螖唯m ; mitochondrial membrane potential ; eIF2伪 ; eukaryotic initiation factor 2伪 ; ER ; endoplasmic reticulum ; FCS ; fetal calf serum ; hPASMC ; human pulmonary artery smooth muscle cell ; HSP
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 May, 2012
• 卷：52
• 期：9
• 页码：1786-1795
• 文件大小：967 K

摘要

Proliferation of vascular smooth muscle cells is a characteristic of pathological vascular remodeling and represents a significant therapeutic challenge in several cardiovascular diseases. Docosahexaenoic acid (DHA), a member of the n-3 polyunsaturated fatty acids, was shown to inhibit proliferation of numerous cell types, implicating several different mechanisms. In this study we examined the molecular events underlying the inhibitory effects of DHA on proliferation of primary human smooth muscle cells isolated from small pulmonary artery (hPASMCs). DHA concentration-dependently inhibited hPASMC proliferation, induced G1 cell cycle arrest, and decreased cyclin D1 protein expression. DHA activated the unfolded protein response (UPR), evidenced by increased mRNA expression of HSPA5, increased phosphorylation of eukaryotic initiation factor 2伪, and splicing of X-box binding protein 1. DHA altered cellular lipid composition and led to increased reactive oxygen species (ROS) production. DHA-induced ROS were dependent on both intracellular Ca²⁺ release and entry of extracellular Ca²⁺_. Overall cellular ROS and mitochondrial ROS were decreased by RU360, a specific inhibitor of mitochondrial Ca²⁺ uptake. DHA-induced mitochondrial dysfunction was evidenced by decreased mitochondrial membrane potential and decreased cellular ATP content. DHA triggered apoptosis as found by increased numbers of cleaved caspase-3- and TUNEL-positive cells. The free radical scavenger Tempol counteracted DHA-induced ROS, cell cycle arrest, induction of UPR, and apoptosis. We conclude that Ca²⁺-dependent oxidative stress is the central and initial event responsible for induction of UPR, cell cycle arrest, and apoptosis in DHA-treated hPASMCs.