Morphine inhibits VEGF expression in myocardial ischemia

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pharmacology

Background:

• Vascular endothelial growth factor (VEGF) promotes collateral circulation, aiding recovery from myocardial ischemia.
• Morphine analgesia is linked to increased infarct size after myocardial ischemia.
• Hypoxia-induced factor 1-alpha (HIF-1alpha) is a key regulator of VEGF expression.

Purpose of the Study:

• To investigate the effect of morphine on myocardial VEGF expression.
• To determine if morphine inhibits hypoxia-induced factor 1-alpha (HIF-1alpha) and associated signaling pathways.
• To elucidate the role of Erk-1,2 MAP kinase and PI3 kinase in morphine's effect on VEGF.

Main Methods:

• In vitro studies using primary rat cardiac myocytes.
• In vivo studies utilizing a rat coronary ligation model.
• Quantitative mRNA and protein analyses including RT-PCR, ELISA, Western immunoblot, EMSA, and immunohistochemistry.

Main Results:

• Morphine decreased hypoxia-induced VEGF mRNA and protein expression in cardiac myocytes via opioid receptors.
• Morphine reduced HIF-1alpha protein and DNA binding activity, and inhibited Erk-1,2 MAP kinase and PI3 kinase (phospho-Akt) activity.
• In vivo, morphine treatment decreased myocardial VEGF, HIF-1alpha, phospho-Erk-1,2, and phospho-Akt expression.

Conclusions:

• Morphine inhibits hypoxia-induced VEGF transcription partly through an HIF-1alpha-mediated mechanism.
• Morphine's inhibition of HIF-1alpha may involve the suppression of ERK 1,2 MAP kinase and PI3 kinase activities.
• These findings suggest a molecular basis for morphine's potential negative impact on myocardial recovery after ischemia.