title: Endothelium-derived neuregulin protects the heart against ischemic injury.
abstract: BACKGROUND
  Removal of cardiac endothelial cells (EC) has been shown to produce significant detrimental effects on the function of adjacent cardiac myocytes, suggesting that EC play a critical role in autocrine/paracrine regulation of the heart. Despite this important observation, the mediators of the protective function of EC remain obscure. Neuregulin (NRG, a member of the epidermal growth factor family) is produced by EC and cardiac myocytes contain receptors (erbB) for this ligand. We hypothesized that NRG is an essential factor produced by EC, which promotes cardioprotection against ischemic injury.
  
  
  RESULTS
  We demonstrate that human cardiac EC express and release NRG in response to hypoxia-reoxygenation. Under conditions where hypoxia--reoxygenation causes significant cardiac myocyte cell death, NRG can significantly decrease apoptosis of isolated adult ventricular myocytes. Coculturing adult murine myocytes with human umbilical vein, murine lung microvascular, or human coronary artery EC can also protect myocytes against hypoxia--reoxygenation--induced apoptosis. These protective effects are abolished by NRG gene deletion or silencing of NRG expression in EC. Finally, endothelium-selective deletion of NRG in vivo leads to significantly decreased tolerance to ischemic insult, as demonstrated by impaired postischemic contractile recovery in a perfused whole-organ preparation and larger infarct sizes after coronary artery ligation.
  
  
  CONCLUSIONS
  Together, these data demonstrate that EC-derived NRG plays an important role in cardiac myocyte protection against ischemic injury in the heart and supports the idea that manipulation of this signaling pathway may be an important clinical target in this setting.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Hedhli
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Huang
authors.forename: April
authors.initials: A
authors.lastname: Kalinowski
authors.forename: Monica
authors.initials: M
authors.lastname: Palmeri
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Hu
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Russell
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse