title: Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload.
abstract: BACKGROUND
  Uric acid (UA) has proven to be a causal agent in endothelial dysfunction in which ROS production plays an important role. Calcium overload in mitochondria can promote the mitochondrial production of ROS. We hypothesize that calcium transduction in mitochondria contributes to UA-induced endothelial dysfunction.
  
  
  RESULTS
  We first demonstrated that high concentrations of UA cause endothelial dysfunction, marked by a reduction in eNOS protein expression and NO release in vitro. We further found that a high concentration of UA increased levels of [Ca2+]mito, total intracellular ROS, H2O2, and mitochondrial O2·-, and Δψmito but not the [Ca2+]cyt level. When the mitochondrial calcium channels NCXmito and MCU were blocked by CGP-37157 and Ru360, respectively, the UA-induced increases in the levels of [Ca2+]mito and total intracellular ROS were significantly reduced. Mitochondrial levels of O2·- and Δψmito were reduced by inhibition of NCXmito but not of MCU. Moreover, inhibition of NCXmito, but not of MCU, blocked the UA-induced reductions in eNOS protein expression and NO release.
  
  
  CONCLUSIONS
  The increased generation of mitochondrial O2·- induced by a high concentration of UA is triggered by mitochondrial calcium overload and ultimately leads to endothelial dysfunction. In this process, the activation of NCXmito is the major cause of the influx of calcium into mitochondria. Our results provide a new pathophysiological mechanism for UA-induced endothelial dysfunction and may offer a new therapeutic target for clinicians.
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, 2011DAV00088, Beijing 100853, PR China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Ka
authors.initials: K
authors.lastname: Qi
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Huang
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Cui
authors.forename: Liyuan
authors.initials: L
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.forename: Jurong
authors.initials: J
authors.lastname: Yang
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.forename: Di
authors.initials: D
authors.lastname: Wu
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000503:physiopathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D033461:Hyperuricemia / Q000139:chemically induced; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D014527:Uric Acid; D009569:Nitric Oxide; D002998:Clonazepam; C079032:CGP 37157; D006861:Hydrogen Peroxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen; D002118:Calcium