Regulation of angiogenesis by MAP kinase pathways during cardiac ischaemia and reperfusion

• Main Author: Miller, Bryan William
• Published: University of Leicester 2003
• Subjects: 612.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490922

Two models of simulated ischaemia/reperfusion were established in the rat cardiac cell line H9c2 and in human umbilical vein endothelial cells (HUVECs). In both cell types, p38 was activated during ischaemia and reperfusion while JNK was only activated during reperfusion. In H9c2 cells, ERK was active during ischaemia and reperfusion while it was not responsive in HUVECs.;The expression of the pro-angiogenic vascular endothelial growth factors (VEGFs) during H9c2 ischaemia/reperfusion was examined. Ischaemia did not have any significant effect on VEGF expression but reperfusion stimulated a strong rise in VEGF-A mRNA levels. This was entirely due to post-transcriptional regulation as there was an increase in VEGF-A mRNA stability but not rise in promoter activity or transcription rate. The increase in VEGF-A mRNA stability was dependent upon activation of the JNK and ERK pathways.;Expression of the VEGF receptors Flt-1 and KDR was studied during ischaemia/reperfusion in HUVECs. While the mRNA levels of both genes remained constant throughout, KDR protein expression was elevated during ischaemia and this was dependent on p38 activation.;Further genes responsive to ischaemia/reperfusion were identified by microarray. Genes found to be induced included the cytoprotective genes neuroglobin and diaphorase 4 and the angiogenesis inhibitor calreticulin. Repressed genes included the potential angiogenesis inhibitor thrombospondin 4.;This study shows that that ischaemia/reperfusion resulted in a rise in pro-angiogenic gene expression and that this is dependent on MAP kinase activity. This suggests that the MAP kinases may play a pivotal role in regulating angiogenesis during cardiac ischaemia/reperfusion.