VEGFR1 (Flt-1+/−) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium

• Published in: Free radical biology & medicine Vol. 42; no. 10; pp. 1487 - 1495
• Main Authors: Thirunavukkarasu, Mahesh, Juhasz, Bela, Zhan, Lijun, Menon, Venugopal P., Tosaki, Arpad, Otani, Hajime, Maulik, Nilanjana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-05-2007
• Subjects: Angiogenesis; Animals; Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors; Cytoprotection - genetics; Endothelial Cells - metabolism; Flt-1; Free radicals; Heart Ventricles - metabolism; Heart Ventricles - pathology; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HO-1; In Vitro Techniques; Ischemia; Ischemic Preconditioning, Myocardial; Mice; Mice, Knockout; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardium; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NF-kappa B - antagonists & inhibitors; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reperfusion; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; RNA, Messenger - metabolism; STAT3 Transcription Factor - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - physiology; Angiogenesis; Reperfusion; Free radicals; Ischemia; Nitric oxide; Myocardium; HO-1; Flt-1
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2007.02.011

This report demonstrates that mice deficient in Flt-1 failed to establish ischemic preconditioning (PC)-mediated cardioprotection in isolated working buffer-perfused ischemic/reperfused (I/R) hearts compared to wild type (WT) subjected to the same PC protocol. WT and Flt-1+/− mice were divided into four groups: (1) WT I/R, (2) WT + PC, (3) Flt-1+/− I/R, and (4) Flt-1+/− + PC. Group 1 and 3 mice were subjected to 30 min of ischemia followed by 2 h of reperfusion and group 2 and 4 mice were subjected to four episodes of 4-min global ischemia followed by 6 min of reperfusion before ischemia/reperfusion. For both wild-type and Flt-1+/− mice, the postischemic functional recovery for the hearts was lower than the baseline, but the recovery for the knockout mice was less compared to the WT mice even in preconditioning. The myocardial infarction and apoptosis were higher in Flt-1+/− compared to wild-type I/R. Flt-1+/− KO mice demonstrated pronounced inhibition of the expression of iNOS, p-AKT & p-eNOS. Significant inhibition of STAT3 & CREB were also observed along with the inhibition of HO-1 mRNA. Results demonstrate that Flt-1+/− mouse hearts are more susceptible to ischemia/reperfusion injury and also document that preconditioning is not as effective as found in WT and therefore suggest the importance of VEGF/Flt-1 signaling in ischemic/reperfused myocardium.