Peptidyl-Prolyl Isomerase 1 Regulates Ca Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na/Ca Exchanger 1 Protein Levels and Function

Overview

Journal J Am Heart Assoc

Specialty Cardiology & Vascular Diseases

Date 2017 Oct 12

PMID 29018025

Citations 5

Authors

Veronica Sacchi

Bingyan J Wang

Dieter Kubli

Alexander S Martinez

Jung-Kang Jin

Roberto Alvarez Jr

Nirmala Hariharan

Christopher Glembotski

Takafumi Uchida

James S Malter

Yijun Yang

Polina Gross

Chen Zhang

Steven Houser

Marcello Rota

Mark A Sussman

Affiliations

Soon will be listed here.

Abstract

Background: Aberrant Ca handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl-prolyl - 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 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 decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) and Na/Ca exchanger 1 protein levels. However, SERCA2a ATPase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1-deficient hearts, suggesting that Pin1 influences SERCA2a function. SERCA2a and Na/Ca exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA2a and Na/Ca exchanger 1 proteins.

Conclusions: Pin1 serves as a modulator of SERCA2a and Na/Ca exchanger 1 Ca 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.

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Peptidyl-Prolyl Isomerase 1 Regulates Ca Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na/Ca Exchanger 1 Protein Levels and Function.

Sacchi V, Wang B, Kubli D, Martinez A, Jin J, Alvarez Jr R J Am Heart Assoc. 2017; 6(10).

PMID: 29018025 PMC: 5721875. DOI: 10.1161/JAHA.117.006837.

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