Journal of Cellular and Molecular Medicine | |
α‐Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway | |
Hyunsoo Kim3  Han-Jong Kim1  Kyunghee Lee3  Jin-Man Kim3  Hee Sun Kim3  Jae-Ryong Kim2  Chae-Myeong Ha1  Young-Keun Choi1  Sun Joo Lee1  Joon-Young Kim1  Robert A. Harris1  Daewon Jeong3  | |
[1] Department of Internal Medicine, Biochemistry and Cell Biology, WCU Program, Research Institute for Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Korea;Department of Biochemistry and Molecular Biology, Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu, Korea;Department of Microbiology, Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu, Korea | |
关键词: vascular smooth muscle cells; vascular calcification; mitochondria; apoptosis; survival; redox status; chronic kidney disease; | |
DOI : 10.1111/j.1582-4934.2011.01294.x | |
来源: Wiley | |
【 摘 要 】
Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D3-induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway.Abstract
【 授权许可】
Unknown
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
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