title: Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury.
abstract: Oncostatin M (OSM) exhibits many unique biological activities by activating the Oβ receptor. However, its role in myocardial ischemia/reperfusion injury (I/R injury) in mice remains unknown. We investigated whether Notch3/Akt signaling is involved in the regulation of OSM-induced protection against cardiac I/R injury. The effects of OSM were assessed in mice that underwent myocardial I/R injury by OSM treatment or by genetic deficiency of the OSM receptor Oβ. We investigated its effects on cardiomyocyte apoptosis and mitochondrial biogenesis and whether Notch3/Akt signaling was involved in the regulation of OSM-induced protection against cardiac I/R injury. The mice underwent 30 min of ischemia followed by 3 h of reperfusion and were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) 72 h before coronary artery ligation. Myocardial infarct size, cardiac function, cardiomyocyte apoptosis and mitochondria morphology in mice that underwent cardiac I/R injury were compared between groups. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through promotion of Notch3 production, thus activating the PI3K/Akt pathway. OSM enhanced mitochondrial biogenesis and mitochondrial function in mice subjected to cardiac I/R injury. In contrast, OSM receptor Oβ knock out exacerbated cardiac I/R injury, decreased Notch3 production, enhanced cardiomyocyte apoptosis, and impaired mitochondrial biogenesis in cardiac I/R injured mice. The mechanism of OSM on cardiac I/R injury is partly mediated by the Notch3/Akt pathway. These results suggest a novel role of Notch3/Akt signaling that contributes to OSM-induced protection against cardiac I/R injury.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Zhijing
authors.initials: Z
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zheng
authors.forename: Cuiting
authors.initials: C
authors.lastname: Qiu
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.forename: Dongdong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac; D053683:Oncostatin M / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D053677:Receptors, Oncostatin M / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006131:Growth Inhibitors; C499373:Notch3 protein, mouse; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D051057:Proto-Oncogene Proteins c-akt