Targeted Overexpression of Sarcolipin in the Mouse Heart Decreases Sarcoplasmic Reticulum Calcium Transport and Cardiac Contractility

Mark T. Ziolo,Sripriya Raman,Natalia N. Petrashevskaya,Honglan Wang,Ganapathy Jagatheesan,Gopal J. Babu,Arnold Schwartz,Muthu Periasamy,Paul M.L. Janssen,David Wieczorek,Debra Wheeler,Poornima Bhupathy

doi:10.1074/jbc.m508998200

Mark T. Ziolo, Sripriya Raman + Show 10 more

Open Access

https://doi.org/10.1074/jbc.m508998200

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Abstract

The role of sarcolipin (SLN) in cardiac physiology was critically evaluated by generating a transgenic (TG) mouse model in which the SLN to sarco(endoplasmic)reticulum (SR) Ca(2+) ATPase (SERCA) ratio was increased in the ventricle. Overexpression of SLN decreases SR calcium transport function and results in decreased calcium transient amplitude and rate of relaxation. SLN TG hearts exhibit a significant decrease in rates of contraction and relaxation when assessed by ex vivo work-performing heart preparations. Similar results were also observed with muscle preparations and myocytes from SLN TG ventricles. Interestingly, the inhibitory effect of SLN was partially relieved upon high dose of isoproterenol treatment and stimulation at high frequency. Biochemical analyses show that an increase in SLN level does not affect PLB levels, monomer to pentamer ratio, or its phosphorylation status. No compensatory changes were seen in the expression of other calcium-handling proteins. These studies suggest that the SLN effect on SERCA pump is direct and is not mediated through increased monomerization of PLB or by a change in PLB phosphorylation status. We conclude that SLN is a novel regulator of SERCA pump activity, and its inhibitory effect can be reversed by beta-adrenergic agonists.

Highlights

SLN is a 31-amino acid protein expressed in both cardiac and skeletal muscle [11, 13,14,15]
Using adenoviral gene transfer into cardiac myocytes, we recently demonstrated that overexpression of SLN resulted in decreased myocyte contractility and calcium handling
Our results show that the expression levels of SERCA2a, PLB, and CSQ were unchanged in the TG ventricle (Fig. 2A) indicating that expression of these proteins was not affected by SLN overexpression

Summary

Introduction

SLN is a 31-amino acid protein expressed in both cardiac and skeletal muscle [11, 13,14,15]. Results presented in this study suggest that SLN directly inhibits the SERCA pump activity, and its inhibitory effect can be reversed upon adrenergic stimulation and increased frequency.

Results

Conclusion