TY - JOUR
T1 - Pressure overload regulates expression of cytokines, γh2ax, and growth arrest-and dna-damage inducible protein 153 via glycogen synthase kinase-3β in ischemic-reperfused hearts
AU - Baban, Babak
AU - Liu, Jun Yao
AU - Mozaffari, Mahmood S.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/1
Y1 - 2013/1
N2 - The growth arrest-and DNA-damage inducible protein 153 (GADD153) regulates both apoptosis and inflammatory response. Importantly, glycogen synthase kinase-3β (GSK-3β) may provide a mechanistic link for cellular expression of GADD153, inflammatory response, and cell death. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion injury associated with significant reduction in phosphorylated (inactive) GSK-3β. This raises the possibility that pressure overload, through a GSK-3β-dependent mechanism, increases GADD153 expression, thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial ischemia reperfusion injury. Accordingly, Langendorff-perfused rat hearts were subjected to global ischemia reperfusion protocol in the absence or presence of the GSK-3β inhibitor, lithium chloride (1 mmol/L), with perfusion pressure set at 80 or 160 cmH2O; normoxic hearts served as controls. Compared with normoxia, an ischemia reperfusion insult increased expressions of proinflammatory cytokines, γH2AX, and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload did the following: (1) reduced interleukin-10 but increased interleukin-17 (cardiomyocytes), without affecting interleukin-23; (2) increased expressions of γH2AX and GADD153; (3) decreased 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolylcarbocyanine iodide (JC-1) aggregates but increased JC-1 monomers (suggestive of reduced mitochondrial membrane potential, ψm); and (4) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Treatment with lithium chloride caused a robust increase in interleukin-10, preserved ψm, and markedly decreased all other parameters with the effect being most prominent for hearts perfused at the high pressure. In conclusion, pressure overload, via a GSK-3β-dependent mechanism, exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of inflammatory response, DNA injury, and GADD153 expression.
AB - The growth arrest-and DNA-damage inducible protein 153 (GADD153) regulates both apoptosis and inflammatory response. Importantly, glycogen synthase kinase-3β (GSK-3β) may provide a mechanistic link for cellular expression of GADD153, inflammatory response, and cell death. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion injury associated with significant reduction in phosphorylated (inactive) GSK-3β. This raises the possibility that pressure overload, through a GSK-3β-dependent mechanism, increases GADD153 expression, thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial ischemia reperfusion injury. Accordingly, Langendorff-perfused rat hearts were subjected to global ischemia reperfusion protocol in the absence or presence of the GSK-3β inhibitor, lithium chloride (1 mmol/L), with perfusion pressure set at 80 or 160 cmH2O; normoxic hearts served as controls. Compared with normoxia, an ischemia reperfusion insult increased expressions of proinflammatory cytokines, γH2AX, and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload did the following: (1) reduced interleukin-10 but increased interleukin-17 (cardiomyocytes), without affecting interleukin-23; (2) increased expressions of γH2AX and GADD153; (3) decreased 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolylcarbocyanine iodide (JC-1) aggregates but increased JC-1 monomers (suggestive of reduced mitochondrial membrane potential, ψm); and (4) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Treatment with lithium chloride caused a robust increase in interleukin-10, preserved ψm, and markedly decreased all other parameters with the effect being most prominent for hearts perfused at the high pressure. In conclusion, pressure overload, via a GSK-3β-dependent mechanism, exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of inflammatory response, DNA injury, and GADD153 expression.
KW - apoptosis
KW - cytokine
KW - glycogen synthase kinase-3β
KW - growth arrest-and DNA-damage inducible protein 153
KW - heart
KW - ischemia reperfusion
KW - necrosis
KW - γH2AX
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U2 - 10.1161/HYPERTENSIONAHA.111.00028
DO - 10.1161/HYPERTENSIONAHA.111.00028
M3 - Article
C2 - 23108649
AN - SCOPUS:84871615801
SN - 0194-911X
VL - 61
SP - 95
EP - 104
JO - Hypertension
JF - Hypertension
IS - 1
ER -