Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications

Abstract

Systolic and diastolic myocardial dysfunction has been demonstrated to be associated with an activation of the circulating and local renin-angiotensin-aldosterone system (RAAS), and with a subsequent inappropriately increased production of reactive oxygen species (ROS). While, at low concentrations, ROS modulate important physiological functions through changes in cellular signalling and gene expression, overproduction of ROS may adversely alter cardiac mechanics, leading to further worsening of systolic and diastolic function. In addition, vascular endothelial dysfunction due to uncoupling of the nitric oxide synthase, activation of vascular and phagocytic membrane oxidases or mitochondrial oxidative stress may lead to increased vascular stiffness, further compromising cardiac performance in afterload-dependent hearts. In the present review, we address the potential role of ROS in the pathophysiology of myocardial and vascular dysfunction in heart failure (HF) and their therapeutic targeting. We discuss possible mechanisms underlying the failure of antioxidant vitamins in improving patients' prognosis, the impact of angiotensin-converting enzyme inhibitors or AT1 receptor blockers on oxidative stress, and the mechanism of the benefit of combination of hydralazine/isosorbide dinitrate. Further, we provide evidence supporting the existence of differences in the pathophysiology of HF with preserved vs. reduced ejection fraction and whether targeting mitochondrial ROS might be a particularly interesting therapeutic option for patients with preserved ejection fraction.

Figure 1

Mortality for patients with heart failure with preserved ejection fraction and heart failure with reduced ejection fraction adjusted for age, gender, aetiology of heart failure, hypertension, diabetes, and atrial fibrillation (with permission from ref.). Copyright © 2012 Oxford University Press.

Figure 2

Superoxide (O₂^·−) is produced from molecular oxygen (O₂) and may react with nitric oxide (^·NO) to form peroxynitrite (ONOO⁻), thereby reducing the bioavailability of nitric oxide. Alternatively, superoxide may be dismutated by superoxide dismutases (SODs) to form hydrogen peroxide (H₂O₂), which is either degraded to water by catalases (CAT) and glutathione peroxidases (GPx), or reacts with free ferrous iron (Fe²⁺), generated by superoxide from ferric iron (Fe³⁺), to form hydroxyl radical (^·OH) in the Fenton reaction, one of the most reactive species in biological systems. The entire reaction cycle is called the Haber–Weiss reaction or cycle.

Figure 3

Enzymatic superoxide sources in heart failure.

Figure 4

Interplay between excitation–contraction (EC) coupling, mitochondrial redox state, and oxidative stress in normal and failing hearts. The Krebs cycle produces NADH, which donates electrons (e⁻) to the electron transport chain (ETC) to promote proton (H⁺) translocation across the inner mitochondrial membrane (IMM). The proton gradient (ΔpH) is harnessed by the F₁F_o ATP synthase to generate ATP. Superoxide anion radicals (^·O₂⁻) are produced at the ETC and dismutated to hydrogen peroxide (H₂O₂) by Mn²⁺-dependent superoxide dismutase (SOD). Hydrogen peroxide is eliminated by enzymes requiring NADPH (i.e. glutathione peroxidase, GPX; and peroxiredoxin, PRX). Reduced form of NADP is regenerated by enzymes facilitating products of the Krebs cycle (i.e. isocitrate dehydrogenase, IDH; malic enzyme, MDH; and transhydrogenase, THG). Ca²⁺ is taken up into mitochondria via a Ca²⁺ uniporter (MCU) and stimulates key enzymes of the Krebs cycle. Ca²⁺ is exported from mitochondria via a Na⁺/Ca²⁺ exchanger (NCLX). During EC coupling, Ca²⁺ is released from the SR via ryanodine receptors (RyR), and due to the close vicinity of the SR to mitochondria, a mitochondrial Ca²⁺ microdomain with very high Ca²⁺ concentrations facilitates Ca²⁺ uptake into mitochondria. Mitochondrial Ca²⁺ uptake during increased physiological workload (i.e. during β-adrenergic stimulation) regenerates NADH and NADPH to match ATP supply to demand (through NADH) and regenerate the antioxidative capacity (through NADPH). In heart failure, decreased SR Ca²⁺ release and increased cytosolic Na⁺ (in part related to an increased late Na⁺ current, late I_Na) impairs mitochondrial Ca²⁺ uptake, which oxidizes NADH and NADPH and thus, provokes energetic deficit and oxidative stress (all changes in heart failure are marked with red arrows). This oxidizes Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII) which in turn phosphorylates RyRs, thereby increasing SR Ca²⁺ leak, and also increases late I_Na, setting in motion a positive feedback loop of impaired EC coupling with contractile dysfunction and arrhythmias, impaired mitochondrial energetics and oxidative stress. Furthermore, CaMKII phosphorylates histone deacetylase 4 (HDAC4), which promotes cardiac hypertrophy through activation of pro-hypertrophic genes in the nucleus. Potential points of intervention in patients with heart failure are late I_Na (by ranolazine), improving SR Ca²⁺ ATPase (SERCA) activity through gene therapy, or by ameliorating mitochondrial ROS emission by Bendavia (SS-31) or MitoQ. GSH, glutathione; TRX, thioredoxin; ΔΨ_m, mitochondrial membrane potential. NCX, Na⁺/Ca²⁺ exchanger; NKA, Na⁺/K⁺ ATPase; NHE, Na⁺/H⁺ exchanger; OMM, outer mitochondrial membrane.

Figure 5

Crosstalk between different cardiovascular ROS sources. Upon agonist-driven activation of NADPH oxidase (e.g. via angiotensin-II-mediated AT1R activation), the enzyme produces superoxide and hydrogen peroxide leading to activation of mitochondrial ROS (mtROS) formation by mitochondrial redox switches (mRS). These mtROS can escape from mitochondria by increased mitochondrial permeability (mPM) involving several pores and channels. In the cytosol these mtROS can activate Nox2 (or Nox1) via redox-sensitive kinases such as protein kinase C (PKC) and tyrosine kinases (cSrc). Likewise Nox- and mitochondria-derived ROS can convert xanthine dehydrogenase to the xanthine oxidase (XO) or lead to eNOS uncoupling further contributing to this vicious circle. Alternatively, this crosstalk starts at the mitochondrial level by excessive mtROS formation during the aging process, a dysregulated ion balance (e.g. in the failing heart) or in response to ischaemia/reperfusion (I/R) damage.

Figure 6

(A) Effects of Vitamin E high and low concentrations on endothelial function of cholesterol fed animals (with permission from ref.). Copyright © 1994 American Society for Clinical Investigation. (B) Effects of Vitamin E treatment on the incidence of heart failure (with permission from ref.). Copyright © 2005 American Medical Association. (C) Effects of Vitamin E treatment on left heart decompensations (with permission from ref.). Copyright © 2005 American Medical Association. (D) Potential pro-oxidative effects of Vitamin E (with permission from ref.). Copyright © 1999 Elsevier Science Ltd. All rights reserved.