Morphine inhibits VEGF expression in myocardial ischemia

S. Roy, S. Balasubramanian, Jinghua Wang, Y. Chandrashekhar, R. Charboneau, Roderick Barke

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)336-344
Number of pages9
Issue number2
StatePublished - Aug 1 2003


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