a-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway

Title
a-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway
Author(s)
정대원김현수[김현수]김한종[김한종]이경희[이경희]김진만[김진만]김희선김재룡하채명[하채명]최명권[최명권]이선주[이선주]김준영[김준영]Robert A. Harris[Robert A. Harris]이인규[이인규]
Keywords
CHRONIC KIDNEY-DISEASE; MUSCLE-CELL CALCIFICATION; MARROW STROMAL CELLS; OXIDATIVE STRESS; PERMEABILITY TRANSITION; CLINICAL-IMPLICATIONS; BONE-RESORPTION; IN-VITRO; ALPHA; APOPTOSIS
Issue Date
201202
Publisher
WILEY-BLACKWELL
Citation
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, v.16, no.2, pp.273 - 286
Abstract
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 a-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.
URI
http://hdl.handle.net/YU.REPOSITORY/29873http://dx.doi.org/10.1111/j.1582-4934.2011.01294.x
ISSN
1582-1838
Appears in Collections:
의과대학 > 미생물학교실 > Articles
의과대학 > 생화학.분자생물학교실 > Articles
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