Open AccessPeptidyl‐Prolyl Isomerase 1 Regulates Ca 2+ Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATP ase and Na 2+ /Ca 2+ Exchanger 1 Protein Levels and Function
Author(s) -
Sacchi Veronica,
Wang Bingyan J.,
Kubli Dieter,
Martinez Alexander S.,
Jin JungKang,
Alvarez Roberto,
Hariharan Nirmala,
Glembotski Christopher,
Uchida Takafumi,
Malter James S.,
Yang Yijun,
Gross Polina,
Zhang Chen,
Houser Steven,
Rota Marcello,
Sussman Mark A.
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.006837
Subject(s) - serca , endoplasmic reticulum , phospholamban , calcium , thapsigargin , contractility , calcium pump , atpase , microbiology and biotechnology , medicine , chemistry , biochemistry , biology , enzyme
Background Aberrant Ca 2+ handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca 2+ handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl‐prolyl cis ‐ trans isomerase peptidyl‐prolyl isomerase 1 (Pin1) is a critical mediator of myocardial hypertrophy development and cardiac progenitor cell cycle. However, the influence of Pin1 on calcium cycling regulation has not been explored. On the basis of these findings, the aim of this study is to define Pin1 as a novel modulator of Ca 2+ handling, with implications for improving myocardial contractility and potential for ameliorating development of heart failure. Methods and Results Pin1 gene deletion or pharmacological inhibition delays cytosolic Ca 2+ decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATP ase ( SERCA 2a) and Na 2+ /Ca 2+ exchanger 1 protein levels. However, SERCA 2a ATP ase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1‐deficient hearts, suggesting that Pin1 influences SERCA 2a function. SERCA 2a and Na 2+ /Ca 2+ exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca 2+ handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA 2a and Na 2+ /Ca 2+ exchanger 1 proteins. Conclusions Pin1 serves as a modulator of SERCA 2a and Na 2+ /Ca 2+ exchanger 1 Ca 2+ handling proteins, with loss of function resulting in impaired cardiomyocyte relaxation, setting the stage for subsequent investigations to assess Pin1 dysregulation and modulation in the progression of heart failure.