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. METHODS AND 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.
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. METHODS AND 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: Catherine M Dreiza; Padmini Komalavilas; Elizabeth J Furnish; Charles R Flynn; Michael R Sheller; Christopher C Smoke; Luciana B Lopes; Colleen M Brophy Journal: Cell Stress Chaperones Date: 2009-07-01 Impact factor: 3.667
Authors: Stephanie Grote-Wessels; Hideo A Baba; Peter Boknik; Ali El-Armouche; Larissa Fabritz; Hans-Jörg Gillmann; Dana Kucerova; Marek Matus; Frank U Müller; Joachim Neumann; Martina Schmitz; Frank Stümpel; Gregor Theilmeier; Jeremias Wohlschlaeger; Wilhelm Schmitz; Uwe Kirchhefer Journal: Cardiovasc Res Date: 2008-05-03 Impact factor: 10.787
Authors: Katrin Wittköpper; Larissa Fabritz; Stefan Neef; Katharina R Ort; Clemens Grefe; Bernhard Unsöld; Paulus Kirchhof; Lars S Maier; Gerd Hasenfuss; Dobromir Dobrev; Thomas Eschenhagen; Ali El-Armouche Journal: J Clin Invest Date: 2010-01-11 Impact factor: 14.808
Authors: Wei Huang; Jialiang Liang; Yuliang Feng; Zhanfeng Jia; Lin Jiang; Wenfeng Cai; Christian Paul; Jianguo G Gu; Peter J Stambrook; Ronald W Millard; Xiao-Lan Zhu; Ping Zhu; Yigang Wang Journal: Exp Cell Res Date: 2018-05-26 Impact factor: 3.905
Authors: Nancy Yu; Michael Kakunda; Victoria Pham; Jennie R Lill; Pan Du; Matthew Wongchenko; Yibing Yan; Ron Firestein; XiaoDong Huang Journal: Mol Cell Biol Date: 2015-02-02 Impact factor: 4.272