Document Detail


Induction of intracellular heat-shock protein 72 prevents the development of vascular smooth muscle cell calcification.
MedLine Citation:
PMID:  22933322     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: 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.
METHODS AND 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.
CONCLUSION: 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:
Tzong-Shi Lu; Kenneth Lim; Guerman Molostvov; Yun-Chun Yang; Szu-Yu Yiao; Daniel Zehnder; Li-Li Hsiao
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-29
Journal Detail:
Title:  Cardiovascular research     Volume:  96     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-04-25     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  524-32     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Case-Control Studies
Cells, Cultured
Core Binding Factor Alpha 1 Subunit / metabolism
Coronary Artery Disease / metabolism*,  pathology
Female
HSP72 Heat-Shock Proteins / antagonists & inhibitors,  genetics,  metabolism*
Heat-Shock Response
Humans
Male
Middle Aged
Muscle, Smooth, Vascular / drug effects,  metabolism*,  pathology
Myocytes, Smooth Muscle / drug effects,  metabolism*,  pathology
Nuclear Proteins / metabolism
Organ Culture Techniques
Phenotype
Quercetin / pharmacology
RNA Interference
RNA, Messenger / metabolism
Renal Insufficiency, Chronic / metabolism*,  pathology
Serum Response Factor / metabolism
Signal Transduction
Trans-Activators / metabolism
Transfection
Up-Regulation
Vascular Calcification / genetics,  metabolism,  pathology,  prevention & control*
Young Adult
Grant Support
ID/Acronym/Agency:
PG/11/66/28982//British Heart Foundation
Chemical
Reg. No./Substance:
0/Core Binding Factor Alpha 1 Subunit; 0/HSP72 Heat-Shock Proteins; 0/Nuclear Proteins; 0/RNA, Messenger; 0/RUNX2 protein, human; 0/SRF protein, human; 0/Serum Response Factor; 0/Trans-Activators; 0/myocardin; 9IKM0I5T1E/Quercetin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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