title: Ursodeoxycholic Acid Attenuates Acute Aortic Dissection Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice Associated with Reduced ROS and Increased Nrf2 Levels.
abstract: OBJECTIVE
  Acute aortic dissection (AAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA) attenuates AAD formation.
  
  
  METHODS
  Angiotensin II (Ang II) was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day) was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days.
  
  
  RESULTS
  Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37) and UDCA markedly reduced the incidence of AAD to 16% (6/37), accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS) and apoptosis of vascular smooth muscle cells (VSMCs) both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91) in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT), thereby inhibiting apoptosis of VSMCs.
  
  
  CONCLUSIONS
  These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Liu
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Xintian
authors.initials: X
authors.lastname: Liu
authors.forename: Xingwei
authors.initials: X
authors.lastname: He
authors.forename: Yujian
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhuxi
authors.initials: Z
authors.lastname: Li
authors.forename: Hesong
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002756:Cholagogues and Choleretics; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D014580:Ursodeoxycholic Acid