title: Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice.
abstract: OBJECTIVE
  Innate and adaptive immune responses are associated with the development of hypertension-induced myocardial hypertrophy and fibrosis. As a result, we investigated whether heat shock protein (HSP) 70, which is a molecule of damage-associated molecular patterns, could induce inflammation in the myocardium and promote the development of hypertension-induced cardiac hypertrophy and fibrosis.
  
  
  RESULTS
  We found that HSP70 serum levels, as well as the amount of HSP70 translocation to the cardiomyocyte membranes and the interstitial space, were elevated in the hypertensive mice caused by abdominal aortic constriction (AAC). Transcriptional inhibition of HSP70 expression by a specific heat shock transcript factor inhibitor, KNK437, reduced the serum level, and the re-distribution of HSP70. It promoted myocardial hypertrophy and cardiac dysfunctions although it protected animals from AAC-induced cardiac fibrosis. On the other hand, the functional antagonism of HSP70 by an anti-HSP70 antibody attenuated AAC-induced cardiac hypertrophy and fibrosis without adverse haemodynamic effects. The cardioprotective effect of the anti-HSP70 antibody was largely attributed to its ability to block AAC-activated immune response in the heart, as was indicated by suppressing the hypertension-enhanced conjugation of HSP70 with toll-like receptor 4, reducing heart-infiltrating macrophages, decreasing the expression of pro-inflammatory factor monocyte chemoattractant protein-1 and profibrotic factor transforming growth factor beta 1, and attenuating pro-hypertrophy signal MAPK P38 and ERK.
  
  
  CONCLUSIONS
  These results indicate that intracellular and extracellular HSP70 have different roles in the regulation of cardiac remodelling and function in response to hypertension. Extracellular HSP70 is a potential therapeutic target against cardiac hypertrophy and fibrosis.
authors.affiliation: The Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Cai
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhang
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yan
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Ma
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Bing-Mu
authors.initials: BM
authors.lastname: Xin
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Lv
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Wang
authors.forename: Zi-Yan
authors.initials: ZY
authors.lastname: Wang
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001559:Benzhydryl Compounds / Q000008:administration & dosage; D001794:Blood Pressure; D006332:Cardiomegaly / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006973:Hypertension / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D011760:Pyrrolidinones / Q000008:administration & dosage; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D001559:Benzhydryl Compounds; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018840:HSP70 Heat-Shock Proteins; C410027:KNK 437; D011760:Pyrrolidinones; C508961:Tgfb1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases