Post-transcriptional regulation of VEGF-A mRNA levels by mitogen-activated protein kinases (MAPKs) during metabolic stress associated with ischaemia/reperfusion

• Published in: Molecular and cellular biochemistry 2012-08, Vol.367 (1-2), p.31-42
• Main Authors: Miller, Bryan W., Hay, Joanna M., Prigent, Sally A., Dickens, Martin
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biochemistry; Biomedical and Life Sciences; Cardiology; Enzyme Activation; Gene Expression Regulation; Genetic aspects; Genetic transcription; Growth factors; Ischemia; Kinases; Life Sciences; MAP Kinase Signaling System; Medical Biochemistry; Messenger RNA; Metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Mitogens; Oncology; Phosphorylation; Promoter Regions, Genetic; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein Processing, Post-Translational; Rats; Reperfusion Injury; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Stress (Physiology); Stress, Physiological; Transcriptional Activation; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-012-1316-9

Angiogenesis is a well-characterised response to the metabolic stresses that occur during ischaemia/reperfusion, but the signalling pathways that regulate it are poorly understood. We tested whether activation of mitogen-activated protein kinases (MAPKs) was involved in regulating the expression of pro-angiogenic growth factors by the metabolic stresses associated with ischaemia/reperfusion in H9c2 rat cardiomyoblasts. Metabolic stress had no effect on vascular endothelial growth factor (VEGF) mRNA levels, but recovery after metabolic inhibition led to a strong induction of VEGF-A mRNA (3.8 ± 0.5-fold at 4 h), a modest rise in VEGF-C mRNA levels (1.7 ± 0.3-fold at 4 h), with no effect on VEGF-B or -D. A VEGF-A promoter reporter construct was unresponsive to metabolic inhibition/recovery and increases in VEGF-A mRNA were not blocked by the transcription inhibitor actinomycin D suggesting that increases in VEGF mRNA were due to enhanced VEGF-A mRNA stability. In addition, studies using reporter constructs demonstrated that regions within the 5′ untranslated region (UTR) contributed to enhanced mRNA stability following recovery from metabolic stress. Increases in VEGF-A mRNA were abolished by inhibition of extracellular signal-regulated kinase or c-jun N-terminal kinase MAPKs, suggesting that these kinases may promote angiogenesis in response to metabolic stress during ischaemia/reperfusion by increasing VEGF-A message stability.