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

Mahesh Thirunavukkarasu, Bela Juhasz, Lijun Zhan, Venugopal P. Menon, Arpad Tosaki, Hajime Otani, Nilanjana Maulik

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1487-1495
Number of pages9
JournalFree Radical Biology and Medicine
Volume42
Issue number10
DOIs
Publication statusPublished - May 15 2007

Keywords

  • Angiogenesis
  • Flt-1
  • Free radicals
  • HO-1
  • Ischemia
  • Myocardium
  • Nitric oxide
  • Reperfusion

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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