title: Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice.
abstract: 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.
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shiroto
authors.forename: Tibor
authors.initials: T
authors.lastname: Turoczi
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhan
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kaga
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Saul
authors.initials: S
authors.lastname: Surrey
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Duan
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.forename: Fumio
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1