title: Endoplasmic reticulum stress-dependent activation of ATF3 mediates the late phase of ischemic preconditioning.
abstract: Ischemic preconditioning (PC) is an adaptive response to transient myocardial ischemia that protects the heart from subsequent ischemia/reperfusion (I/R) injury. However, the mechanisms underlying its cardioprotective effects remain unclear. Myocardium of adult male C57/BL6 mice, preconditioned by 6 cycles of 4 minute coronary occlusion and reperfusion, showed nuclear translocation of ATF3 and ATF6 and PERK phosphorylation 30 min after PC. The abundance of ER proteins, ATF3 and ATF4 was increased 24h after PC; however, there was no evidence of IRE-1 activation in WT or ER-stress activated indicator (ERAI) mice expressing XBP-1-Venus fusion protein. PC-induced nuclear translocation of ATF3 was attenuated in transgenic mice with cardiac-restricted overexpression of inducible ATF6. Ischemic PC increased the abundance of inducible nitric oxide synthase, cyclooxygenase-2, heme oxygenase-1 and aldose reductase to levels similar between WT and ATF3-null hearts; however, the increase in IL-6 and ICAM-1 was exaggerated in ATF3-null hearts. Genetic deletion of ATF3 did not increase infarct size in non-preconditioned hearts but abolished the cardioprotective effects of PC. Larger infarct size in preconditioned ATF3-null hearts was associated with greater neutrophil infiltration in the myocardium, but no ATF3-dependent changes in the total or relative abundance of inflammatory monocytes were observed. Ischemic PC activates the unfolded protein response (UPR) and the activation of ATF3 by ER stress is essential for the cardioprotective effects of late PC.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Brooks
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: James
authors.initials: J
authors.lastname: McCracken
authors.affiliation: Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA. Electronic address: aruni@louisville.edu.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D015850:Interleukin-6 / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D015850:Interleukin-6
keywords: ATF3; Infarct size; Ischemic preconditioning; Unfolded protein response; inflammatory response