title: Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy.
abstract: BACKGROUND
  Hspa1a and Hspa1b genes encode stress-inducible 70-kDa heat shock proteins (Hsp70) that protect cells from insults such as ischemia. Mice with null mutations of both genes (KO) were generated, and their cardiac phenotype was explored.
  
  
  RESULTS
  Heart rate and blood pressures were normal in the KO mice. Hearts from KO mice were more susceptible to both functional and cellular damage by ischemia/reperfusion. Cardiac hypertrophy developed in Hsp70-KO mice. Ca2+ transients in cardiomyocytes of KO mice showed a delayed (120%) calcium decline and decreased sarcoplasmic reticulum calcium content. Cell shortening was decreased by 35%, and rates of contraction and relaxation were slower by 40%. These alterations can be attributed to the absence of Hsp70 because viral expression of Hsp70 in KO cultured cardiomyocytes restored these parameters. One mechanism underlying myocyte dysfunction could be decreased SERCA2a expression. This hypothesis was supported by a prolonged calcium decline and decreased SERCA2a protein. Viral SERCA2a expression restored contractility and Ca2+ transients. We examined the involvement of Jun N-terminal kinase (JNK), p38-mitogen-activated protein kinase (p38-MAPK), Raf-1, and extracellular signal-regulated kinase (ERK) in SERCA2a downregulation and the cardiac phenotype of KO mice. Levels of phosphorylated JNK, p38-MAPK, Raf-1, and ERK were elevated in KO hearts. Activation of the Raf-1-ERK pathway in normal cardiomyocytes resulted in decreased SERCA2a.
  
  
  CONCLUSIONS
  Absence of Hsp70 leads to dysfunctional cardiomyocytes and impaired stress response of Hsp70-KO hearts against ischemia/reperfusion. In addition, deletion of Hsp70 genes might induce cardiac dysfunction and development of cardiac hypertrophy through the activation of JNK, p38-MAPK, Raf-1, and ERK.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0618, USA.
authors.forename: Yun-Kyung
authors.initials: YK
authors.lastname: Kim
authors.forename: Jorge
authors.initials: J
authors.lastname: Suarez
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McDonough
authors.forename: Christa
authors.initials: C
authors.lastname: Boer
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000502:physiology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000032:analysis / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000502:physiology; D010641:Phenotype; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis / Q000502:physiology
chemical_list: D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium