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 D(3) -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.