title: Induction of intracellular heat-shock protein 72 prevents the development of vascular smooth muscle cell calcification.
abstract: OBJECTIVE
  Vascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease (CKD) and coronary artery disease (CAD). Osteo/chondrocytic transformation and simultaneous dedifferentiation of smooth muscle cells (SMCs) are important in the pathogenesis of VC. Heat-shock protein 72 (HSP72) is a cardioprotective inducible heat-shock protein that functions as a molecular chaperone. However, its role in the development of accelerated vascular dysfunction and calcification is largely unexplored.
  
  
  RESULTS
  We describe for the first time marked reduction in HSP72 expression in arteries from patients with CKD and CAD, compared with healthy controls, in vivo. Induction of HSP72 by heat-shock treatment (HST) significantly prevented the development of calcification of human aortic smooth muscle cells (HA-SMCs), in vitro. These anti-calcific effects were abolished following treatment with both quercetin, an HST inhibitor, and HSP72 siRNA knockdown. Induction of HSP72 suppressed Cbfa-1-dependent osteo/chondrocytic transformation and stabilized SMC contractile phenotype through the myocardin-serum response factor (SRF) pathway. Co-immunoprecipitation studies demonstrated physical association between SRF and HSP72. Furthermore, organ culture of arteries from CKD and CAD patients showed that these arteries retained their ability to induce HSP72 following HST, despite initially reduced expression.
  
  
  CONCLUSIONS
  Our study shows for the first time that intracellular HSP72 may function as a central regulator of molecular pathways involved in the development of VC. We suggest treatment strategies that up-regulate HSP72 as a new approach to inhibit VC.
authors.affiliation: Department of Medicine, Renal Division,  Brigham and Women's Hospital, Harvard Medical School, Room 120, 41 Ave Louis Pasteurb, Boston, MA 02115,  USA.
authors.forename: Tzong-Shi
authors.initials: TS
authors.lastname: Lu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lim
authors.forename: Guerman
authors.initials: G
authors.lastname: Molostvov
authors.forename: Yun-Chun
authors.initials: YC
authors.lastname: Yang
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Yiao
authors.forename: Daniel
authors.initials: D
authors.lastname: Zehnder
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Hsiao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D005260:Female; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010641:Phenotype; D011794:Quercetin / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D055815:Young Adult; D000099251:Myocardin
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050884:HSP72 Heat-Shock Proteins; D009687:Nuclear Proteins; D011794:Quercetin; D012333:RNA, Messenger; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C493709:RUNX2 protein, human; C476858:SRF protein, human