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Published on: November 17, 2014
Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice
Sankar Addya1, Keisuke Shiroto, Tibor Turoczi
1Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
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.
Insights
Vascular Endothelial Growth Factor (VEGF) signaling via the Flt-1 receptor is crucial for the protective effects of ischemic preconditioning in the heart. Heterozygous Flt-1 knockout mice showed diminished benefits from preconditioning, highlighting VEGF-Flt-1
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Ischemic Heart Disease Research
Background:
- Ischemic stress triggers angiogenic signaling pathways in the myocardium.
- Vascular Endothelial Growth Factor (VEGF) and its receptor Flt-1 (VEGFR1) play a role in angiogenesis.
- Understanding VEGF-Flt-1 signaling is critical for addressing clinical issues related to ischemic heart conditions.
Purpose of the Study:
- To investigate the significance of VEGF-Flt-1 signaling in ischemic preconditioned (PC) myocardium.
- To identify candidate genes involved in VEGF signaling under ischemic stress.
- To determine the role of Flt-1 receptor in mediating the protective effects of PC.
Main Methods:
- Utilized heterozygous Flt-1 knockout (KO) mice and wild type (WT) CD-1 mice.
- Exposed mice to ischemia (30 min) and reperfusion (2 h) with and without preconditioning (PC).
- Employed DNA microarrays to analyze myocardial gene expression changes.
Main Results:
- Heterozygous Flt-1 KO mice exhibited significantly reduced left ventricular functional recovery after PC compared to WT mice.
- The beneficial effects of PC were diminished in KO mice, indicating impaired protective signaling.
- Gene expression analysis revealed downregulation of key genes like Gro1, HSPs, IKK beta, CSF-1, and annexin A7 in KO mice.
Conclusions:
- VEGF-Flt-1 receptor signaling is essential for the effectiveness of ischemic preconditioning in the myocardium.
- The study identifies specific genes potentially regulated by VEGF-Flt-1 signaling during PC.
- These findings underscore the importance of the VEGF-Flt-1 pathway in cardiac protection against ischemic injury.
