Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes

Highlights

• Redox-sensitive alterations in Na⁺- and Ca²⁺-handling are relevant to the heart.

• PKA, PKC, CaMKII, and Na⁺- and Ca²⁺-transporters and channels are involved.

• ROS have physiological and pathophysiological relevance.

Abstract

In this review article we give an overview of current knowledge with respect to redox-sensitive alterations in Na⁺ and Ca²⁺ handling in the heart. In particular, we focus on redox-activated protein kinases including cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), as well as on redox-regulated downstream targets such as Na⁺ and Ca²⁺ transporters and channels. We highlight the pathological and physiological relevance of reactive oxygen species and some of its sources (such as NADPH oxidases, NOXes) for excitation—contraction coupling (ECC). A short outlook with respect to the clinical relevance of redox-dependent Na⁺ and Ca²⁺ imbalance will be given.

Introduction

Heart failure (HF) is a highly prevalent disease syndrome that is characterized by an inability of the heart to provide sufficient blood flow to meet the body's needs. Various disease states such as (i) vascular dysfunction, (ii) diseased heart valves, (iii) hypertension, (iv) infection/inflammation, (v) primary cardiomyopathies (such as dilated cardiomyopathy, DCM), or even (vi) toxic factors such as (radio-)chemotherapy can cause HF. Failing hearts are usually characterized by a progressively deteriorated contractile function (HF with reduced ejection fraction, HFrEF) except for the situation when contractility is normal despite symptoms (HF with preserved ejection fraction, HFpEF).

On a cellular level, cardiac myocytes that represent the functional core element of the heart reveal dramatically impaired functional properties. In that regard, it is now accepted that an impaired intracellular Ca²⁺ handling can causally contribute to contractile dysfunction [1]. A typical example of a relevant defect in Ca²⁺ handling that can contribute to impaired contractility is diastolic Ca²⁺ leakage from the sarcoplasmic reticulum (SR). The SR represents the intracellular Ca²⁺ store of the cardiac myocyte. Diastolic SR Ca²⁺ leakage leads to a progressive SR Ca²⁺ depletion. In turn, less Ca²⁺ can be released from the SR during systole. This results in a diminished increase in cytosolic Ca²⁺ during systole (i.e., decreased systolic Ca²⁺ transient). As a consequence, insufficient activation of myofilaments results in an impaired myocyte contraction. SR Ca²⁺ leak is a result of “leaky” Ca²⁺ release channels (ryanodine receptors, RyR2). Insufficient sealing of the SR is a typical feature in human and animal failing cardiac myocytes [2]. The underlying mechanisms are complex and may involve increased RyR2 phosphorylation by activated serine/threonine protein kinases [3], [4]. Moreover, the concentration of reactive oxygen species (ROS) is elevated in failing hearts and might further amplify redox-regulated protein kinase's activity at the RyR2 [5], [6]. In addition, it is becoming increasingly clear that ROS themselves can alter broad aspects of Na⁺ and Ca²⁺ handling in healthy and diseased cardiac myocytes [7], [8], [9], [10], [11]. For instance, RyR2s are rich in cystein residues and are ready targets to redox modifications. In fact, ROS were shown to directly induce pathological SR Ca²⁺ leak in failing myocytes by redox modification [12]. Myocytes from failing hearts reveal a pattern of impaired Na⁺ and Ca²⁺ handling in the face of increased ROS generation. It is therefore tempting to speculate that hampered Na⁺ and Ca²⁺ handling is due to disturbed ROS homeostasis. In turn, redox-modified Ca²⁺ handling may contribute to the disease progression, which would render it a novel and promising therapeutical target.

In that regard, this review aims to give a comprehensive overview of current knowledge with respect to redox-sensitive alterations in cardiac Na⁺ and Ca²⁺ handling. It particularly focuses on redox-activated protein kinases including cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), as well as on redox-regulated downstream targets such as Na⁺ and Ca²⁺ transporters and channels. We will try to highlight the physiological and pathological relevance of reactive oxygen species and some of its chosen sources (such as NADPH oxidases, NOXes) for excitation—contraction coupling (ECC). Finally, a short outlook with respect to the clinical relevance of redox-dependent Na⁺ and Ca²⁺ imbalance will be given.