Peroxisome Proliferator-Activated Receptor-gamma Coactivator-1 alpha Inhibits Vascular Calcification Through Sirtuin 3-Mediated Reduction of Mitochondrial Oxidative Stress

摘要

Aims: Vascular calcification is associated with cardiovascular death in patients with chronic kidney disease (CKD). Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) plays an important role in various cardiovascular diseases. However, its role in vascular calcification remains unknown. Results: Adenine-induced rat CKD model was used to induce arterial medial calcification. The level of PGC-1 alpha decreased in abdominal aorta of CKD rats. Overexpression of PGC-1 alpha significantly ameliorated calcium deposition in rat abdominal aorta, isolated carotid rings, and cultured vascular smooth muscle cells (VSMCs). Mitochondrial reactive oxygen species (mtROS) increased in calcifying aorta and VSMCs. Upregulation of PGC-1 alpha inhibited, whereas PGC-1 alpha depletion promoted beta-glycerophosphate-induced mtROS production and calcium deposition. Moreover, PGC-1 alpha increased superoxide dismutase 1 (SOD1) and SOD2 contents in vivo and in vitro, whereas SOD2 deletion eliminated PGC-1 alpha-mediated mtROS change and promoted calcium deposition. Mechanistically, sirtuin 3 (SIRT3) expression declined in calcifying aorta and VSMCs, while PGC-1 alpha overexpression restored SIRT3 expression. Inhibition of SIRT3 by 3-TYP or siRNA (small interfering RNA) reduced PGC-1 alpha-induced upregulation of SOD1 and SOD2, and abolished the protective effect of PGC-1 alpha on calcification of VSMCs. Importantly, PGC-1 alpha was reduced in calcified femoral arteries in CKD patients. In phosphate-induced human umbilical arterial calcification, upregulation of PGC-1 alpha attenuated calcium nodule formation, while this protective effect was abolished by SIRT3 inhibitor. Innovation: We showed for the first time that PGC-1 alpha is an important endogenous regulator against vascular calcification. Induction of PGC-1 alpha could be a potential strategy to treat vascular calcification in CKD patients. Conclusions: PGC-1 alpha protected against vascular calcification by SIRT3-mediated mtROS reduction. Antioxid. Redox Signal. 00, 000-000.