Oxidative Stress as a Target of Cardiac Remodeling: History
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Contributor:
Danilo Martins
,
Leonardo Rufino Garcia
,
Diego Aparecido Rios Queiroz
,
Taline Lazzarin
,
Carolina Rodrigues Tonon
,
Paola da Silva Balin
,
Bertha Furlan Polegato
,
Sergio Alberto Rupp de Paiva
,
Paula Schmidt Azevedo
,
Marcos Ferreira Minicucci
,
Leonardo Zornoff

Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that clinically manifest as changes in the heart’s size, mass, geometry, and function after different stimuli. It is important to emphasize that remodeling plays a pathophysiological role in the onset and progression of ventricular dysfunction and subsequent heart failure. Therefore, strategies to mitigate this process are critical. Different factors, including neurohormonal activation, can regulate the remodeling process and increase cell death, alterations in contractile and regulatory proteins, alterations in energy metabolism, changes in genomics, inflammation, changes in calcium transit, metalloproteases activation, fibrosis, alterations in matricellular proteins, and changes in left ventricular geometry, among other mechanisms.

  • antioxidants
  • heart failure
  • cardiac remodeling

1. Introduction

Cardiac remodeling plays a pathophysiological role in the onset and progression of ventricular dysfunction and subsequent heart failure. Therefore, strategies to mitigate this process are critical. Recently, the role of reactive oxygen species and oxidative stress as modulators of remodeling has been gaining attention.

2. Cardiac Remodeling

Cardiac remodeling is defined as molecular, cellular, and interstitial changes manifested clinically as alterations in the heart’s size, shape, and function after different stimuli [1].
It is worth highlighting the differentiation between physiological (compensatory) cardiac remodeling and pathological (maladaptive) remodeling.
The important point is that numerous injury triggers are recognized, including cardiac infarction, hypertension, diabetes, valvular diseases, toxicity, inflammation, arrhythmia, genetic cardiopathies, and other conditions [1]. It is important to emphasize that the main cellular element altered in remodeling is the cardiomyocyte. Still, other cells are involved in the process, such as fibroblasts, immune system cells, and coronary vasculature cells [2].
Another relevant issue is that cardiac remodeling may result in progressive ventricular dysfunction, the clinical presentation of heart failure, and cardiovascular death. Therefore, reversing or preventing further remodeling is critical to improving the prognosis associated with different cardiac injuries.
Several pathways can modulate cardiac remodeling, including neurohormonal activation, increase in cell death, alterations in contractile and regulatory proteins, alterations in energy metabolism, changes in genomics, inflammation, changes in calcium transit, metalloprotease activation, fibrosis, alterations in matricellular proteins, and changes in left ventricular geometry, among other mechanisms [1][3]. In recent years, however, due to its relevance and therapeutic potential, oxidative stress has gained prominence as a critical modulator of cardiac remodeling [4], as shown in Figure 1.
Figure 1. Natural history of cardiac remodeling.

3. Oxidative Stress as a Potential Modulator of Cardiac Remodeling

Oxidative stress is the disproportion between the formation of reactive oxygen species (ROS) and the inactivation capacity of the cellular endogenous antioxidant system. It may result from increased production of ROS and dysfunctions of the antioxidant defense [5]. The balance between ROS production and its inactivation is recognized as the redox state [6].
Reactive oxygenated or nitrogenated species (ROS/RNS) include free radicals and nonradicals with high reactivity. They are represented by hydrogen peroxide, superoxide anion radical, singlet oxygen, and hydroxyl radical [6][7]. Reactive nitrogen species, such as nitric oxide, peroxynitrite, iron, copper, and sulfur, are also encountered [8][9]. The biochemical interaction between ROS and RNS, products of oxidative stress, with nucleic acids, lipids, and proteins, determines structural changes and functions responsible for several pathological processes, including cardiovascular disease and cardiac remodeling. Despite the widely described deleterious biological effects of ROS and RNS, they are also responsible for other processes related to homeostasis, such as participation in cellular immune defense, cell signaling, and biosynthetic reactions, for example [10].
Superoxide radical anion results from a one-electron reduction of oxygen by oxidases, like nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase or NOX), xanthine oxidase (XO), and cyclooxygenase (COX). It can also be formed in the mitochondrial electron transport chain during oxidative phosphorylation responsible for ATP formation [11]. Superoxide anion is an active nucleophile that can react to positively charged centers and dismutate, yielding molecular oxygen and hydrogen peroxide [7].
Hydrogen peroxide can be generated from superoxide and in the presence of oxidases (urate oxidase, glucose oxidase, D-amino acid oxidase) which catalyze two-electron transfer to molecular oxygen. Hydrogen peroxide can produce highly reactive radicals by interacting with hemeprotein structure with an iron release, enzyme inactivation, and oxidation of DNA, lipids, sulfur groups, and keto acids.
On the other hand, the hydroxyl radical is responsible for the oxidative damage due to its aggressiveness. It results from Fenton-type reactions and radiolysis of water [12]. This radical is the most powerful oxidizing and can interact with DNA, proteins, lipids, amino acids, sugars, and metals [7]. Molecular oxygen has oxidative power due to the remotion of spin restriction of oxygen [12].
Another important reactive species is peroxynitrite. It is formed by the reaction of superoxide anion radical and endogenous nitric oxide (NO) [13], involved in vasodilation and neurotransmission. NO is synthesized from L-arginine, oxygen, and NADPH by enzymes belonging to the nitric oxide synthase (NOS) class [7]. Peroxynitrite, in turn, is a very reactive and damaging nitrogen species and a powerful oxidant to many biomolecules. Peroxynitrite can be decomposed to hydroxyl radicals, and its protonated form can act as depleting sulfhydryl groups, causing oxidative derangement on several biomolecules like hydroxyl radicals. It also can cause DNA damage through breaks, protein oxidation, and nitration of aromatic amino acid moieties in protein structure [7].
Under physiological situations, superoxide anion and hydrogen peroxide are not very reactive, and hydroperoxides proved almost stable. Their reactivity is enhanced by the presence of hemeproteins and low molecular weight transition metal chelates, which may produce more reactive species such as hydroxyl radical or ferryl hemeprotein radical. The latter participates in the formation of alkoxyl and peroxyl radicals. However, suppose the antioxidant system does not act at the proper sites. In that case, oxidative damage of enzymes, ion channels, structural proteins, and membrane lipids may occur, impairing many cell functions, bringing pathological consequences, and even cell death [7]. For example, global ischemia in the heart leads to a 250% increase in reactive oxygen species [14]. In this way, the presence of ROS and RNS in pathological status and not properly counterbalanced by the antioxidant defenses is strictly related to cytotoxicity, which can explain, at a molecular level, the occurrence of cardiac remodeling and cardiac dysfunction.
The deleterious action of ROS is directly involved in the pathogenesis of cardiac tissues. They promote myocardial growth, extracellular matrix remodeling, and cellular dysfunction by activating hypertrophy signaling kinases and transcription factors [6].
Stimuli such as angiotensin II, bradykinins, endothelins, α-adrenergic stimulation, and ROS act on cardiac G-protein [15]. After the described stimulation, hypertrophic signaling pathways are activated [16]. It is also well known that G-protein coupled receptor activation can lead to ROS generation [5]. Thus, ROS, by stimulating G-protein and being a by-product of its action, promote hypertrophic growth signaling in ventricular myocytes [15].
ROS also stimulates cellular apoptosis, signaling kinase-1, a redox-sensitive kinase, which, when overexpressed, leads to nuclear factor kappa beta (NF-ĸB)-induced hypertrophy by specifically related gene expression [6][15].
Inside the cardiomyocyte nucleus, ROS may cause DNA strand breaks, activating the enzyme poly (ADP-ribose) polymerase-1 (PARP-1), which then regulates the expression of a variety of inflammatory mediators involved in cardiac remodeling progression [6].
The previously described hydrogen peroxide, an important ROS, can activate a few kinase signaling pathways related to hypertrophy and apoptosis. These effects are mediated by extracellular signal-regulated kinase 1/2 (ERK 1/2), c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase, protein kinase B (Akt), and mitogen-activated protein kinase (MAPK). Akt, MAPK, JNK, and p38 mitogen-activated protein kinase are involved in apoptosis, and ERK 1/2 is related to hypertrophy.
The extracellular matrix (ECM) is another potential target for the deleterious action of ROS. ECM comprises a well-organized function network of macromolecules that provides structural support for the cells and tissues and with a significant role in health and disease [17]. ROS can affect ECM by stimulating the proliferation of cardiac fibroblasts [15], resulting in fibrosis and matrix remodeling. Another described interaction is based on ROS action activation matrix metalloproteinases (MMPs) [6]. They also stimulate transcription factors such as NF-ĸB and activator protein-1 to activate MMP expression [5]. Furthermore, MMPs play a pivotal role in normal tissue remodeling processes, such as cell migration, invasion, proliferation, and apoptosis [17], and have been demonstrated to be elevated in failing hearts [6], which makes them the target of potential therapeutic interventions [18].
Oxidative stress is also an important driving force, leading to changes in the cellular cytoskeleton that accompany ventricular remodeling [19]. As part of the cellular cytoskeleton apparatus, microtubules are cylindrical polymers of α/β-tubulin heterodimers that form a complex network throughout the cytoplasm [20]. Oxidative stress then leads to cysteine oxidation of microtubules, and GTP-tubulin incorporation into these damaged and oxidized sites facilitates a pathogenic shift from a sparse microtubule network into a dense, aligned network with a remarkable cellular contractile failure [14].
Another detrimental effect carried out by excessive ROS occurs in ryanodine receptors (RyRs), localized to the sarcoplasmic reticulum (SR) [21]. They are responsible for calcium release from SR during excitation–contraction coupling in striated muscle cells [22].
ROS promotes RyRs activity and inhibits SR calcium-adenosine triphosphatase 2 (SERCA-2) activity, resulting in calcium overload and reduced myofilament calcium sensitivity, leading to contractile dysfunction [21]. Most studies indicate that the oxidation of thiol (SH) groups of RyRs is directly responsible for ROS’s effects [23]. It has been demonstrated that the open probability of cardiac muscle RyRs is increased in the presence of superoxide, hydrogen peroxide, and hydroxyl radical [24]. Data indicate ROS can irreversibly inactivate RyRs with calcium overload and contractile dysfunction [25].
Mitochondria, the cell powerhouse, is a key point to understanding the interface between ROS and cardiac failure and remodeling. These organelles play an important role in maintaining cellular redox balance. Electron transport chain complexes, in charge of ATP synthesis, are a major source of ROS which then are counterbalanced by antioxidant defense systems [5]. Indeed, mitochondrial or antioxidant protein disturbances have been associated with cardiac hypertrophy. ROS can also affect ATP levels, as evidenced by a study that related the status of energy metabolism in myocardial infarction with significantly impaired ATP levels [26]. In this way, mitochondria react to ischemic injury by producing increased levels of ROS, leading to a perverse cycle of energy metabolism and mitochondrial dysfunction [21].
Besides being a relevant source of ROS, mitochondria can also be affected by them, with macromolecules damaged at or near the site of their formation [6]. This organelle has its genomic system, mitochondrial DNA (mtDNA), a closed circular double-stranded molecule responsible for controlling mitochondrial function with factors that regulate its transcription and replication [27]. In turn, failing hearts have increased ROS generation associated with mitochondrial damage and dysfunction. This might be explained by some details related to the organelle itself.
Some features of mitochondria make them more susceptible to oxidative stress. They do not have a complex chromatin organization with histone proteins, which act as defense barriers against ROS, they have a limited repair activity against mtDNA damage, and a large part of superoxide formed inside mitochondria cannot pass through the membranes, causing significant functional impairment [6].
Considering the mechanisms of oxidative stress involved in the pathophysiology of cardiac remodeling, some biomarkers may have a prognostic value in patients with heart failure [28][29][30][31][32]. A study with 843 patients evaluated 37 biomarkers from different domains, including oxidative stress, in patients with heart failure at hospital admission and after 24 h [30]. Among the biomarkers, changes in myeloperoxidase (MPO) were related to outcomes in heart failure with preserved eject fraction patients. Another biomarker, growth differentiation factor-15 (GDF-15), is a cytokine of the transforming growth factor beta (TGF-β) family that is produced by cardiac myocytes in response to oxidative stress [33]. A Chinese observational study showed that this biomarker is an independent predictor of mortality in patients with heart failure with low ejection fraction [31]. In addition, indoxyl sulfate (IS), a gut-derived uremic toxin, increases endothelial ROS production and decreases glutathione levels in endothelial cells [34]. In an observational study with patients submitted to radiofrequency catheter ablation, IS was an independent predictor of the recurrence of atrial fibrillation (AF) [32].
Despite the association between some markers of oxidative stress and prognosis, not even all markers have the same prediction. In a similar study with patients submitted to radiofrequency catheter ablation for AF, high levels of soluble advanced glycation end product receptors (sRAGE) were an independent predictor of the recurrence of AF only in diabetic patients [35]. The same association was not present in patients without diabetes in the same study. Another recent study with 53 patients analyzed the role of different biomarkers in patients with heart failure [36].
Therefore, most evidence suggests that oxidative stress is an important modulator of the cardiac remodeling process in different models.

This entry is adapted from the peer-reviewed paper 10.3390/antiox11122371

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