title: Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress.
abstract: Oxidative/nitrative stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Notch1 participates in the regulation of cardiogenesis and cardiac response to hypertrophic stress, but the function of Notch1 signaling in MI/R has not been explored. This study aims to determine the role of Notch1 in MI/R, and investigate whether Notch1 confers cardioprotection. Notch1 specific small interfering RNA (siRNA, 20 μg) or Jagged1 (a Notch ligand, 12 μg) was delivered through intramyocardial injection. 48 h after injection, mice were subjected to 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress), 24 h (for infarct size and cardiac function), or 2 weeks (for cardiac fibrosis and function) of reperfusion. Cardiac-specific Notch1 knockdown resulted in significantly aggravated I/R injury, as evidenced by enlarged infarct size, depressed cardiac function, increased myocardial apoptosis and cardiac fibrosis. Downregulation of Notch1 increased expression of inducible NO synthase (iNOS) and gp(91phox), enhanced the production of NO metabolites and superoxide, as well as their cytotoxic reaction product peroxynitrite. Moreover, Notch1 blockade also reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, and increased expression of PTEN, a key phosphatase involved in the regulation of Akt phosphorylation. In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury. These data indicate that Notch1 signaling protects against MI/R injury partly though PTEN/Akt mediated anti-oxidative and anti-nitrative effects.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an 710032, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Pei
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Yu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xue
authors.forename: Yunping
authors.initials: Y
authors.lastname: Guo
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Hong
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Qu
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C497762:Notch1 protein, mouse; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D051881:Receptor, Notch1; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse