A change of heart: oxidative stress in governing muscle function?

Abstract

Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

Keywords: Contractile proteins; Diastolic stiffness; Heart failure; Oxidative stress; Passive tension; Post-translational modifications; Titin.

Fig. 1

Pressure–volume loop characteristics in heart failure with reduced ejection fraction (green) (a) and heart failure with preserved ejection fraction (red) (b). Curved arrow depicts the steeper end-systolic pressure–volume relationship in heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction

Fig. 2

Major redox modifications of cysteine and tyrosine side chains. Further details of the reactions are given in the text

Fig. 3

An overview of the main causes of oxidative stress and the induction of oxidative damage in muscle. Abbreviations of causes and modified proteins discussed in the present review: xanthine oxidase (XO), NADPH oxidases (Nox), dihydrobiopterin (BH2), tetrahydrobiopterin (BH4), uncoupled endothelial nitric oxide synthase (eNO synthase), nitric oxide (NO). Free radicals: superoxide (O ₂ ⁻), hydroxyl radical (OH•), hydrogen peroxide (H ₂ O ₂), particulate guanylyl cyclase (pGC), soluble guanylyl (sGC), cyclic guanosine monophosphate; (cGMP), cGMP-dependent protein kinase-G (PKG), phosphorylation (P), phospholamban (PLB), sarcoplasmic reticulum (SR), calcium transport ATPase (SERCA), RyR2, calcium (Ca ²⁺), plasma membrane Ca²⁺ ATPase (PMCA), L-type calcium channel (LTCC), reactive oxygen species (ROS)

Fig. 4

The effect of oxidative stress on titin-based passive stiffness. The top panel illustrates the different segments of the titin chain (N2BA and N2B isoforms) in a half-sarcomere and illustrates oxidative damage in several regions of titin. a Titin-based passive tension in the heart can be tuned by phosphorylation of the titin spring elements N2-Bus and PEVK by the following kinases: protein kinase-A (PKA); protein kinase-G (PKG); protein kinase-Cα (PKCα); extracellular signal-regulated kinase 2 (ERK2); Ca²⁺/calmodulin-dependent protein kinase-IIδ (CaMKII). b Schematic illustration of increased titin-based passive stiffness due to reduced PKG-dependent phosphorylation of the titin N2-Bus element in failing human hearts due to oxidative stress. c Under oxidizing conditions, disulfide bonds in the titin N2-Bus are promoted, thus increasing titin-based passive stiffness. d. Under oxidative conditions, S-glutathionylation of cysteines in unfolded titin immunoglobulin (Ig)-domains (due to sarcomere stretch) inhibits domain refolding and thereby reduces titin stiffness. Under oxidative conditions, phosphorylation of Ig-domains and S-glutathionylation of cysteines may or may not inhibit domain refolding. The effect of these modifications together is unknown