Troponin I phosphorylation in human myocardium in health and disease.

P J M Wijnker,A M Murphy,J Van Der Velden,G J M Stienen

doi:10.1007/s12471-014-0590-4

P J M Wijnker, A M Murphy + Show 2 more

Open Access

https://doi.org/10.1007/s12471-014-0590-4

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Abstract

Cardiac troponin I (cTnI) is well known as a biomarker for the diagnosis of myocardial damage. However, because of its central role in the regulation of contraction and relaxation in heart muscle, cTnI may also be a potential target for the treatment of heart failure. Studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on cTnI (i.e. site-specific phosphorylation). This is caused by altered expression and/or activity of kinases and phosphatases during heart failure development. It is not known whether these (transient) alterations in cTnI phosphorylation are beneficial or detrimental. Knowledge of the effects of site-specific cTnI phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure. In this review we focus on the role of cTnI phosphorylation in the healthy heart upon activation of the beta-adrenergic receptor pathway (as occurs during increased stress and exercise) and as a modulator of the Frank-Starling mechanism. Moreover, we provide an overview of recent studies which aimed to reveal the functional consequences of changes in cTnI phosphorylation in cardiac disease.

Highlights

Cardiac troponin I and its binding partner cardiac troponin T are the biomarkers of choice for the diagnosis of myocardial damage [1, 2]
CTnI is degraded by calcium-sensitive proteases such as calpain I [3] and Cardiac troponin I (cTnI) fragments are released in the blood where they can be detected via the sensitive assays that are used in practice worldwide
In this review we focus on the role of cTnI phosphorylation in the healthy and diseased heart upon activation of the beta-adrenergic receptor pathway and as a modulator of the Frank-Starling mechanism, which reflects the ability of the heart to increase stroke volume with an increase in ventricular filling

Summary

Introduction

Cardiac troponin I (cTnI) and its binding partner cardiac troponin T (cTnT) are the biomarkers of choice for the diagnosis of myocardial damage [1, 2]. In addition to activated (phosphorylated) Ca2+-handling proteins, PKA-mediated cTnI phosphorylation at Serines 23 and 24 (Ser23/24, human sequence) represents a central mechanism controlling cardiomyocyte force development and relaxation, independent of the intracellular Ca2+ concentration. This results in decreased cTnI-Ser23/24 phosphorylation [18,19,20,21] and increased myofilament Ca2+ sensitivity [18, 20] in patients with ischaemic and dilated heart failure compared with non-failing donors.

Results

Conclusion