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.

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

“…Therefore, since the sGC activator reduces oxidative stress, improved cardiomyocyte stiffness could be related, in part, to reduced titin oxidation. The reversible oxidative modifications previously found in the various I-band titin regions have been shown to modify titin-based stiffness also in isolated human cardiomyocytes (Linke and Hamdani, 2014;Beckendorf and Linke, 2015;Breitkreuz and Hamdani, 2015). Disulfide bond formation in the cardiac-specific N2-Bus region appeared to decrease N2B extensibility, stiffen the titin molecule, and increase cardiomyocyte F passive (Grutzner et al, 2009).…”

High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes

“…causes depletion of SR calcium as a result of PLN‐independent inhibition of SERCA (Zima and Blatter ). Also, S‐glutathionylation (protein modifications by oxidative stress) of troponin I increases calcium sensitivity (Breitkreuz and Hamdani ). FGF23‐induced ROS formation might therefore explain the observed changes in calcium fluxes in cardiomyocytes.…”

“…In cardiomyocytes, ROS increase the open probability of RyRs, followed by its inactivation (Holmberg et al 1991), and prolonged exposure of cardiomyocytes to O 2 À. causes depletion of SR calcium as a result of PLN-independent inhibition of SERCA (Zima and Blatter 2006). Also, S-glutathionylation (protein modifications by oxidative stress) of troponin I increases calcium sensitivity (Breitkreuz and Hamdani 2015). FGF23-A B Figure 6.…”

The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases

“…ROS negatively affects the disposition of myocardial calcium, may induce arrhythmia, and can contribute to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis (Burgoyne et al 2012a ; Wagner et al 2013 ). ROS and nitric oxide (NO) produced from these sources are oxygen-/nitrogen-based chemical species with a high reactivity and include free radicals such as superoxide ion (O2 •-), hydroxyl radical (•OH), and peroxy radicals (ROO•), as well as non-radicals that are nevertheless able to generate free radicals, such as hydrogen peroxide (H2O2), nitroxyl, and NO (Breitkreuz and Hamdani 2015 ). A diminished capacity of nitric oxide synthase (NOS) to generate NO (Pitocco et al 2010 ; Sena et al 2013 ) is accompanied by increased oxidative stress during diabetic vascular dysfunction (Giugliano et al 1996 ).…”