title: Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways.
abstract: Microvascular endothelial cells (CMECs) oxidative damage resulting from hypoxia/reoxygenation (H/R) injury is responsible for microcirculation perfusion disturbances and the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. Here, we studied the effects and mechanisms of liraglutide on CEMCs oxidative damage, focusing in particular on calcium overload-triggered free radical injury signals and the GLP-1R/PI3K/Akt/survivin survival pathways. The results indicate that H/R increased IP3R expression but reduced SERCA2a expression, which rapidly raised intracellular Ca(2+) levels, subsequently leading to Ca(2+)-dependent xanthine oxidase (XO) activation, reactive oxygen species (ROS) production and the cellular apoptosis of CMECs. However, liraglutide pretreatment abrogated Ca(2+)-mediated oxidative apoptosis. Furthermore, liraglutide regulated the rate of IP3R/SERCA2a gene transcription and conserved SERCA2a-ATPase activity via the maintenance of ATP production under H/R, which drove excessive Ca(2+) reflux to the sarcoplasmic reticulum (SR) and inhibited Ca(2+) release from the SR, ultimately restoring Ca(2+) homeostasis. Furthermore, the regulatory role of liraglutide on Ca(2+) balance in conjunction with its up-regulation of superoxide dismutase, glutathione and glutathione peroxidase collectively scavenged the excess ROS under H/R. Moreover, we showed that liraglutide strengthened Akt phosphorylation and subsequently survivin expression. In addition, both the blockade of the GLP-1R/PI3K/Akt pathways and the siRNA-mediated knockdown of survivin abolished the protective effects of liraglutide on SR-Ca(2+) function and CMECs oxidative apoptosis. In summary, this study confirmed that H/R induced CMECs oxidative damage through the SR-Ca(2+)-XO-ROS injury signals and that liraglutide pretreatment may suppress such CMECs damage through the PI3K/Akt/survivin pathways.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Burn surgery and Plastic surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Radiotherapy, Beijing Cancer Hospital, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China. Electronic address: cyundai@vip.163.com.
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000503:physiopathology; D000069450:Liraglutide / Q000008:administration & dosage*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D020011:Protective Agents / Q000008:administration & dosage; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020011:Protective Agents; D017382:Reactive Oxygen Species; D000069450:Liraglutide
keywords: Apoptosis; CMECs; Calcium homeostasis; Liraglutide; PI3K/Akt pathway; ROS; Survivin; XO