title: Cardioprotective actions of Notch1 against myocardial infarction via LKB1-dependent AMPK signaling pathway.
abstract: AMP-activated protein kinase (AMPK) signaling pathway plays a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. Notch1 signaling in the adult myocardium is also activated in response to ischemic stress. However, the relationship between Notch1 and AMPK signaling pathways during ischemia remains unclear. We hypothesize that Notch1 as an adaptive signaling pathway protects the heart from ischemic injury via modulating the cardioprotective AMPK signaling pathway. C57BL/6J mice were subjected to an in vivo ligation of left anterior descending coronary artery and the hearts from C57BL/6J mice were subjected to an ex vivo globe ischemia and reperfusion in the Langendorff perfusion system. The Notch1 signaling was activated during myocardial ischemia. A Notch1 γ-secretase inhibitor, dibenzazepine (DBZ), was intraperitoneally injected into mice to inhibit Notch1 signaling pathway by ischemia. The inhibition of Notch1 signaling by DBZ significantly augmented cardiac dysfunctions caused by myocardial infarction. Intriguingly, DBZ treatment also significantly blunted the activation of AMPK signaling pathway. The immunoprecipitation experiments demonstrated that an interaction between Notch1 and liver kinase beta1 (LKB1) modulated AMPK activation during myocardial ischemia. Furthermore, a ligand of Notch1 Jagged1 can significantly reduce cardiac damage caused by ischemia via activation of AMPK signaling pathway and modulation of glucose oxidation and fatty acid oxidation during ischemia and reperfusion. But Jagged1 did not have any cardioprotections on AMPK kinase dead transgenic hearts. Taken together, the results indicate that the cardioprotective effect of Notch1 against ischemic damage is mediated by AMPK signaling via an interaction with upstream LKB1.
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States; The First Affiliated Hospital, Jilin University, Changchun 130012, China.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States; The First Affiliated Hospital, Jilin University, Changchun 130012, China.
authors.forename: Nanhu
authors.initials: N
authors.lastname: Quan
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States; The First Affiliated Hospital, Jilin University, Changchun 130012, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Chu
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Cates
authors.affiliation: The First Affiliated Hospital, Jilin University, Changchun 130012, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital, Jilin University, Changchun 130012, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States. Electronic address: jli3@umc.edu.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Cardioprotection; LKB1; Myocardial infarction; Notch1