TY - JOUR
T1 - Morphine inhibits VEGF expression in myocardial ischemia
AU - Roy, S.
AU - Balasubramanian, S.
AU - Wang, Jinghua
AU - Chandrashekhar, Y.
AU - Charboneau, R.
AU - Barke, Roderick
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Background. Vascular endothelial growth factor (VEGF) may contribute to the resolution of myocardial ischemia by stimulating collateral circulation. Morphine analgesia after myocardial ischemia is thought to increase infarct size. We hypothesize that morphine inhibits myocardial VEGF expression by inhibiting hypoxia-induced factor 1α (HIF-1α) and the signal transduction mechanisms involving Erk-1,2 MAP kinase (p42/p44), and PI3 kinase activity (phospho-Akt). Methods. (1) In vitro: primary cultures of rat cardiac myocytes; (2) in vivo: rat coronary ligation model; (3) mRNA measurement: real-time reverse transcriptase-polymerase chain reaction; (4) protein measurements: enzyme-linked immunosorbent assay, Western immunoblot, electromobility shift assay (EMSA), and immunohistochemistry. Results. Using rat cardiac myocytes in vitro, we show that morphine: (1) decreases hypoxia-induced VEGF121 and VEGF165 mRNA expression and VEGF protein concentration through an opioid receptor mechanism; (2) decreases HIF-1α protein expression (immunoblot) and nuclear protein binding to the VEGF HIF-1α DNA response element (EMSA); and (3) inhibits phospho-Erk-1,2 MAP kinase (immunoblot) and phospho-Akt kinase activity (immunoblot). Using a rat coronary ligation model, we show that morphine treatment: (1) decreases myocardial VEGF protein expression (immunohistochemistry); (2) decreases HIF-1α protein expression (immunoblot); and (3) decreases phospho-Erk-1,2 and phospho-Akt expression. Conclusions. (1) Morphine inhibits hypoxia-induced VEGF transcription, in part, through an HIF-1α-mediated mechanism and (2) morphine inhibition of hypoxia-induced HIF-1α may be mediated by inhibition of ERK 1,2 MAP kinase activity and PI3 kinase activity.
AB - Background. Vascular endothelial growth factor (VEGF) may contribute to the resolution of myocardial ischemia by stimulating collateral circulation. Morphine analgesia after myocardial ischemia is thought to increase infarct size. We hypothesize that morphine inhibits myocardial VEGF expression by inhibiting hypoxia-induced factor 1α (HIF-1α) and the signal transduction mechanisms involving Erk-1,2 MAP kinase (p42/p44), and PI3 kinase activity (phospho-Akt). Methods. (1) In vitro: primary cultures of rat cardiac myocytes; (2) in vivo: rat coronary ligation model; (3) mRNA measurement: real-time reverse transcriptase-polymerase chain reaction; (4) protein measurements: enzyme-linked immunosorbent assay, Western immunoblot, electromobility shift assay (EMSA), and immunohistochemistry. Results. Using rat cardiac myocytes in vitro, we show that morphine: (1) decreases hypoxia-induced VEGF121 and VEGF165 mRNA expression and VEGF protein concentration through an opioid receptor mechanism; (2) decreases HIF-1α protein expression (immunoblot) and nuclear protein binding to the VEGF HIF-1α DNA response element (EMSA); and (3) inhibits phospho-Erk-1,2 MAP kinase (immunoblot) and phospho-Akt kinase activity (immunoblot). Using a rat coronary ligation model, we show that morphine treatment: (1) decreases myocardial VEGF protein expression (immunohistochemistry); (2) decreases HIF-1α protein expression (immunoblot); and (3) decreases phospho-Erk-1,2 and phospho-Akt expression. Conclusions. (1) Morphine inhibits hypoxia-induced VEGF transcription, in part, through an HIF-1α-mediated mechanism and (2) morphine inhibition of hypoxia-induced HIF-1α may be mediated by inhibition of ERK 1,2 MAP kinase activity and PI3 kinase activity.
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U2 - 10.1067/msy.2003.247
DO - 10.1067/msy.2003.247
M3 - Article
C2 - 12947338
AN - SCOPUS:0042829165
SN - 0039-6060
VL - 134
SP - 336
EP - 344
JO - Surgery
JF - Surgery
IS - 2
ER -