TY - JOUR
T1 - Endoplasmic reticulum stress-dependent activation of ATF3 mediates the late phase of ischemic preconditioning
AU - Brooks, Alan C.
AU - Guo, Yiru
AU - Singh, Mahavir
AU - McCracken, James
AU - Xuan, Yu Ting
AU - Srivastava, Sanjay
AU - Bolli, Roberto
AU - Bhatnagar, Aruni
N1 - Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 24. h 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.
AB - 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 24. h 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.
KW - ATF3
KW - Infarct size
KW - Inflammatory response
KW - Ischemic preconditioning
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=84924102606&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924102606&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2014.08.011
DO - 10.1016/j.yjmcc.2014.08.011
M3 - Article
C2 - 25151953
AN - SCOPUS:84924102606
SN - 0011-393X
VL - 76
SP - 138
EP - 147
JO - Current Therapeutic Research - Clinical and Experimental
JF - Current Therapeutic Research - Clinical and Experimental
ER -