title: Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model.
abstract: OBJECTIVE
  Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it.
  
  
  METHODS
  Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed.
  
  
  RESULTS
  Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group.
  
  
  CONCLUSIONS
  We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Oki
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Md Majedul
authors.initials: MM
authors.lastname: Islam
authors.affiliation: Department of Biology, Appalachian State University, Boone, NC, USA.
authors.forename: Chishimba Nathan
authors.initials: CN
authors.lastname: Mowa
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Tanzila
authors.initials: T
authors.lastname: Khatun
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sakuramoto
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kamiyama
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Centre for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Mizutani
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D019332:Endothelin-1 / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C036757:lipopolysaccharide B; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
keywords: Endothelin receptor antagonist (SB-209670); Endotoxemic heart; Lipopolysaccharide; Vascular endothelial growth factor