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

Hyunsoo Kim, Han Jong Kim, Kyunghee Lee, Jin Man Kim, Hee Sun Kim, Jae Ryong Kim, Chae Myeong Ha, Young Keun Choi, Sun Joo Lee, Joon Young Kim, Robert A. Harris, Daewon Jeong, In Kyu Lee

Research output: Contribution to journalArticle

45 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)273-286
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2012

    Fingerprint

Keywords

  • Apoptosis
  • Chronic kidney disease
  • Mitochondria
  • Redox status
  • Survival
  • Vascular calcification
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Kim, H., Kim, H. J., Lee, K., Kim, J. M., Kim, H. S., Kim, J. R., Ha, C. M., Choi, Y. K., Lee, S. J., Kim, J. Y., Harris, R. A., Jeong, D., & Lee, I. K. (2012). α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway. Journal of Cellular and Molecular Medicine, 16(2), 273-286. https://doi.org/10.1111/j.1582-4934.2011.01294.x