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

• Published in: Journal of cellular and molecular medicine 2012-02, Vol.16 (2), p.273-286
• Main Authors: Kim, Hyunsoo, Kim, Han‐Jong, Lee, Kyunghee, Kim, Jin‐Man, Kim, Hee Sun, Kim, Jae‐Ryong, Ha, Chae‐Myeong, Choi, Young‐Keun, Lee, Sun Joo, Kim, Joon‐Young, Harris, Robert A., Jeong, Daewon, Lee, In‐Kyu
• Format: Article
• Language: English
• Subjects: Acids; AKT protein; Animals; Antioxidants; Aorta; Apoptosis; Apoptosis - drug effects; Atherosclerosis; Axl protein; Axl Receptor Tyrosine Kinase; Calcification; Calcification (ectopic); Calcium - metabolism; Cardiovascular diseases; Caspase 3 - metabolism; Caspase 9 - metabolism; Caspase-9; Cell survival; Cells, Cultured; Cholecalciferol - pharmacology; chronic kidney disease; Cytochrome; Cytochrome c; Cytochromes c; Cytosol; Dehydrogenases; Diabetes; DNA Fragmentation; Down-regulation; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Kidney diseases; Kidney Diseases - pathology; Lipoic acid; Male; Membrane potential; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Morbidity; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Original; Oxidative stress; Phosphates - pharmacology; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reagents; Receptor Protein-Tyrosine Kinases - metabolism; redox status; Renal function; Smooth muscle; Sodium; Structure-function relationships; survival; Thioctic Acid - metabolism; vascular calcification; Vascular Calcification - metabolism; Vascular Diseases - genetics; Vascular Diseases - metabolism; vascular smooth muscle cells; Vitamin D3
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/j.1582-4934.2011.01294.x

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.