title: Therapeutic efficacy of apelin on transplanted mesenchymal stem cells in hindlimb ischemic mice via regulation of autophagy.
abstract: Mesenchymal stem cells (MSCs)-based therapy provides a promising avenue for the management of peripheral arterial disease (PAD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment. Apelin has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Here we demonstrated that apelin promoted functional survival of AD-MSCs in ischemic hindlimbs and provoked a synergetic effect with AD-MSCs to restore hindlimb blood perfusion and limb functions. Further in vitro studies revealed that a biphasic response in autophagy was induced by apelin in AD-MSCs during hypoxia and hypoxia/reoxygenation (H/R) stages to exert cytoprotective effects against H/R injury. Mechanistically, apelin increased the viability of AD-MSCs via promoting protective autophagy during hypoxia, which was accompanied with activation of AMPK and inhibition of mammalian target of rapamycin (mTOR). To the contrary, apelin suppressed autophagic cell death during reoxygenation, which was accompanied with activation of Akt and inhibition of Beclin1. Our findings indicated that apelin facilitated AD-MSCs-based therapy in PAD, possibly through promoting survival of AD-MSCs by way of autophagy regulation. Our data support the promises of apelin as a novel strategy to improve MSC-based therapy for PAD, possibly through autophagy modulation in MSCs.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Cardiology, Armed Police Corps Hospital of Shaanxi, Xi'an, Shaanxi 710032, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Cardiology, the 175th Hospital of Chinese PLA, the Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D054392:Adipokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000073861:Apelin; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D007273:Injections, Intramuscular; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D000071186:Beclin-1; D036341:Intercellular Signaling Peptides and Proteins; D049452:Green Fluorescent Proteins; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases