title: Novel role of HAX-1 in ischemic injury protection involvement of heat shock protein 90.
abstract: BACKGROUND
  Ischemic heart disease is characterized by contractile dysfunction and increased cardiomyocyte death, induced by necrosis and apoptosis. Increased cell survival after an ischemic insult is critical and depends on several cellular pathways, which have not been fully elucidated.
  
  
  OBJECTIVE
  To test the hypothesis that the anti-apoptotic hematopoietic lineage substrate-1-associated protein X-1 (HAX-1), recently identified as regulator of cardiac Ca cycling, also may ameliorate cellular injury with an ischemic insult.
  
  
  RESULTS
  We report that cardiac ischemia/reperfusion injury is associated with significant decreases in HAX-1 levels ex vivo and in vivo. Accordingly, overexpression of HAX-1 improved contractile recovery, coupled with reduced infarct size, plasma troponin I level, and apoptosis. The beneficial effects were associated with decreased endoplasmic reticulum (ER) stress response through specific inhibition of the inositol-requiring enzyme (IRE-1) signaling pathway, including its downstream effectors caspase-12 and the transcription factor C/EBP homologous protein. Conversely, HAX-1 heterozygous-deficient hearts exhibited increases in infarct size and IRE-1 activity. The inhibitory effects of HAX-1 were mediated by its binding to the N-terminal fragment of the heat shock protein 90 (Hsp90). Moreover, HAX-1 sequestered Hsp90 from IRE-1 to the phospholamban-sarcoplasmic/endoplasmic reticulum calcium ATPase complex. The HAX-1 regulation was further supported by loss of IRE-1 inhibition in presence of the Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin.
  
  
  CONCLUSIONS
  Cardiac ischemia-reperfusion injury is associated with decreases in HAX-1 levels. Consequently, overexpression of HAX-1 promotes cardiomyocyte survival, mediated by its interaction with Hsp90 and specific inhibition of IRE-1 signaling at the ER/sarcoplasmic reticulum.
authors.affiliation: Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
authors.forename: Chi Keung
authors.initials: CK
authors.lastname: Lam
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vafiadaki
authors.forename: Stela M
authors.initials: SM
authors.lastname: Florea
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ren
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Nathan
authors.initials: N
authors.lastname: Robbins
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D019210:Troponin I / Q000097:blood; D000099211:Phospholamban
chemical_list: D016227:Benzoquinones; D015415:Biomarkers; D002118:Calcium; D002135:Calcium-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019210:Troponin I; D000099211:Phospholamban; C491295:Hs1bp1 protein, mouse; C112765:tanespimycin; C486556:Ern2 protein, mouse