title: Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling.
abstract: BACKGROUND
  Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling.
  
  
  RESULTS
  Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1-PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1.
  
  
  CONCLUSIONS
  Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1-PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vafiadaki
authors.forename: Stela M
authors.initials: SM
authors.lastname: Florea
authors.forename: Vivek P
authors.initials: VP
authors.lastname: Singh
authors.forename: Weizhong
authors.initials: W
authors.lastname: Song
authors.forename: Chi Kung
authors.initials: CK
authors.lastname: Lam
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Pritchard
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.forename: Kobra
authors.initials: K
authors.lastname: Haghighi
authors.forename: Patricia
authors.initials: P
authors.lastname: Rodriguez
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Despina
authors.initials: D
authors.lastname: Sanoudou
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050886:HSP20 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D050886:HSP20 Heat-Shock Proteins; D054645:Protein Phosphatase 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban