Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice.
This study attempts to address an important clinical issue by identifying potential candidates of VEGF signaling through Flt-1 receptor that trigger angiogenic signal under ischemic stress. To determine the significance of VEGF-Flt-1 (VEGFR1) signaling in ischemic preconditioned (PC) myocardium, we used heterozygous Flt-1 knockout (KO) mice to dissect the pathway and identify candidate genes involved in VEGF signaling. DNA microarrays were employed to detect, characterize and distinguish altered myocardial gene expression by comparing between wild type (WT) CD-1 and heterozygous Flt-1 KO mice when exposed to ischemia (30 min) and reperfusion (2 h). Moreover, KO mice demonstrated reduced beneficial effects of PC when compared to the WT with PC. In the KO and WT mice, the % recovery of the left ventricular developed pressure and the maximum first derivative of the developed pressure after ischemia/reperfusion without PC were similar. However, when animals were subjected to PC, the left ventricular functional recovery throughout the reperfusion period was significantly lower in KO mice than in WT mice. These results indicate for the first time that in the heterozygous Flt-1 KO mice, PC is not as effective as that found in WT. This observation may be due to downregulation of several important genes such as growth-regulated oncogene 1 (Gro1), heat shock proteins (HSP), I kappa B kinase beta (IKK beta), colony-stimulating factor-1 (CSF-1) and annexin A7, suggesting the importance of VEGF-Flt-1 receptor signaling during PC.
Addya
Sankar
S
Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Shiroto
Keisuke
K
Turoczi
Tibor
T
Zhan
Lijun
L
Kaga
Shigeaki
S
Fukuda
Shoji
S
Surrey
Saul
S
Duan
Li-Juan
LJ
Fong
Guo-Hua
GH
Yamamoto
Fumio
F
Maulik
Nilanjana
N
D000818:Animals; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006579:Heterozygote; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function / Q000235:genetics
D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1