title: Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-κB and Keap-1/Nrf-2 signaling pathways.
abstract: OBJECTIVE
  Clinical application of cellular therapy for cardiac regeneration is significantly hampered by the low retention of engrafted cells, mainly attributable to the poor microenvironment dominated by inflammation and oxidative stress in the host's infarcted myocardium. This study aims at investigating whether liver X receptor (LXR) agonist T0901317 will improve survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts.
  
  
  RESULTS
  Noninvasive in vivo bioluminescence imaging and histological staining showed that LXR agonist T0901317 improved the retention and survival of intramyocardially injected AD-MSCs. Moreover, combined therapy of LXR agonist and AD-MSCs inhibited host cardiomyocyte apoptosis, reduced fibrosis, and improved cardiac function, while it concomitantly decreased inflammatory cytokines (e.g., tumor necrosis factor-α and interleukin-6) and increased growth factor (e.g., vascular endothelial growth factor and basic fibroblast growth factor) expression in infarct myocardium. To reveal possible mechanisms, AD-MSCs were subjected to hypoxia/serum deprivation (H/SD) injury to simulate ischemic conditions in vivo. The LXR agonist (10(-7) mM) improved AD-MSC survival under H/SD condition. Western blot revealed that the LXR agonist reduced TLR4, TRAF-6, and MyD88 protein expression, inhibited IκBα phosphorylation and NF-κB-p65 nuclear translocation, which resulted in accelerated Keap-1 protein degradation, enhanced Nrf-2 nuclear translocation, and increased HO-1 protein expression.
  
  
  CONCLUSIONS
  LXR agonist can enhance the functional survival of transplanted AD-MSCs in infarcted myocardium, at least partially, via modulation of the TLR4/NF-κB and Keap-1/Nrf-2 signaling pathways. Moreover, combined therapy of LXR agonist and AD-MSCs has a synergetic effect on cardiac repair and functional improvement after infarction.
authors.affiliation: 1 Department of Cardiology, PLA General Hospital , Beijing, China .
authors.forename: Yabin
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Kazim
authors.initials: K
authors.lastname: Narsinh
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.forename: Xing
authors.initials: X
authors.lastname: Qin
authors.forename: Rongqing
authors.initials: R
authors.lastname: Zhang
authors.forename: Congye
authors.initials: C
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage; D000072019:Kelch-Like ECH-Associated Protein 1; D000071518:Liver X Receptors; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D017202:Myocardial Ischemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006845:Hydrocarbons, Fluorinated; D000072019:Kelch-Like ECH-Associated Protein 1; D000071518:Liver X Receptors; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C493487:Tlr4 protein, mouse