Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release.
Autophagy is a dynamic and highly regulated process of self-digestion responsible for cell survival and reaction to oxidative stress. As oxidative stress is increased in uremia and is associated with vascular calcification, we studied the role of autophagy in vascular calcification induced by phosphate. In an in vitro phosphate-induced calcification model of vascular smooth muscle cells (VSMCs) and in an in vivo model of chronic renal failure, autophagy was inhibited by the superoxide dismutase mimic MnTMPyP, superoxide dismutase-2 overexpression, and by knockdown of the sodium-dependent phosphate cotransporter Pit1. Although phosphate-induced VSMC apoptosis was reduced by an inhibitor of autophagy (3-methyladenine) and knockdown of autophagy protein 5, calcium deposition in VSMCs was increased during inhibition of autophagy, even with the apoptosis inhibitor Z-VAD-FMK. An inducer of autophagy, valproic acid, decreased calcification. Furthermore, 3-methyladenine significantly promoted phosphate-induced matrix vesicle release with increased alkaline phosphatase activity. Thus, autophagy may be an endogenous protective mechanism counteracting phosphate-induced vascular calcification by reducing matrix vesicle release. Therapeutic agents influencing the autophagic response may be of benefit to treat aging or disease-related vascular calcification and osteoporosis.
Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
Xiao-Yan
XY
Dai
Ming-Ming
MM
Zhao
Yan
Y
Cai
Qing-Cong
QC
Guan
Ying
Y
Zhao
Youfei
Y
Guan
Wei
W
Kong
Wei-Guo
WG
Zhu
Ming-Jiang
MJ
Xu
Xian
X
Wang
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D061945:Caspase Inhibitors / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010710:Phosphates / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology; D061205:Vascular Calcification / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000099156:Superoxide Dismutase 2
D000225:Adenine; D000469:Alkaline Phosphatase; D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D000071187:Autophagy-Related Protein 5; D061945:Caspase Inhibitors; D008665:Metalloporphyrins; D010710:Phosphates; D011506:Proteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D013482:Superoxide Dismutase; D014635:Valproic Acid; D000099156:Superoxide Dismutase 2; C545865:Atg5 protein, rat; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; C493588:Slc20a1 protein, rat; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C025946:3-methyladenine