antioxidants Review Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation 1, 1,2, 2, Gyeoung Jin Kang y, Eun Ji Kim y and Chang Hoon Lee * 1 Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] (G.J.K.); [email protected] (E.J.K.) 2 College of Pharmacy, Dongguk University, Seoul 04620, Korea * Correspondence: [email protected]; Tel.: +82-31-961-5213 Equally contributed. y Received: 11 November 2020; Accepted: 9 December 2020; Published: 10 December 2020 Abstract: Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation. Keywords: cardiac fibrosis; NRF2; lipoxins; resolvins; maresins; neuroprotectins 1. Introduction Cardiovascular disease is the leading cause of death worldwide [1]. Cardiac fibrosis is a major factor leading to the progression of myocardial infarction and heart failure [2]. Cardiac fibrosis is characterized by the net accumulation of extracellular matrix proteins in the cardiac stroma and ultimately impairs cardiac function [3]. Therefore, interest in substances with cardioprotective activity continues. It has been emphasized that antioxidant activity by nuclear factor erythropoietin 2 related factor 2 (NRF2) is essential for cardiac protection by unsaturated essential fatty acids such as DHA and EPA. Recently, there are increasing reports that NRF2 is regulated by specialized pro-resolving lipids (SPMs) originated from docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA). However, there are not many reports on the effect of NRF2 regulation on cardiac fibrosis by SPMs. Thus, in this review, we would like to summarize the relationship between SPMs and NRF2 in cardiac fibrosis so far. 2. Cardiac Fibrosis and Its Mediators 2.1. Cardiac Fibrosis Cardiac fibrosis is a natural compensatory process that occurs before the symptoms of heart failure. This is indicated by changes in the structure of the ventricles with increased volume and altered chamber configuration. This condition exhibits several characteristic histological features, such as cardiomyocyte hypertrophy and apoptosis, myofibroblast proliferation, and extracellular matrix (ECM) alterations. Cardiac fibrosis occurs when fibroblasts are activated into myofibroblasts, and the amount of ECM protein increases, altering scar tissue formation and the remodeling of the ECM [4] (Figure1). Collagen Antioxidants 2020, 9, 1259; doi:10.3390/antiox9121259 www.mdpi.com/journal/antioxidants Antioxidants 2020, 9, x FOR PEER REVIEW 2 of 28 Cardiac fibrosis occurs when fibroblasts are activated into myofibroblasts, and the amount of Antioxidants 2020, 9, 1259 2 of 27 ECM protein increases, altering scar tissue formation and the remodeling of the ECM [4] (Figure 1). Collagen accumulated through these processes affects both systolic and diastolic function and continuouslyaccumulated throughreduces theseheart processesfunction [3]. affects Cardiac both systolicfibrosis andis part diastolic of the function normal and ageing continuously process. However,reduces heart this function process [is3]. accelerated Cardiac fibrosis by many is part card ofiovascular the normal diseases, ageing process. including However, diabetes, this high process blood is pressure,accelerated and by manymyocardial cardiovascular infarction diseases, (MI), including as well diabetes, as ischemic, high blood dilated, pressure, and and hypertrophic myocardial cardiomyopathyinfarction (MI), as [5]. well as ischemic, dilated, and hypertrophic cardiomyopathy [5]. Figure 1. SchematicSchematic diagrams diagrams depicting depicting the the mechanisms mechanisms of of SPMs SPMs in in alleviating alleviating cardiac cardiac fibrosis fibrosis in Ang-II-infused mice. Irisin Irisin activate activatedd and and accelerated accelerated the the translocation translocation of Nrf2 Nrf2 to to the the nucleus, nucleus, thereby thereby reducing oxidative stress and countering the ROSROS/TGF-/TGF-β1/Smad2/31/Smad2/3 pro-fibrotic pro-fibrotic pathway (modified (modified fromfrom Chen et al. [6]). [6]). Cardiac fibrosis fibrosis can be divided into three types.types. Regional Regional fibrosis fibrosis (also known as reparative fibrosis)fibrosis) occursoccurs when when the the aff ectedaffected area area is replaced is repl byaced scar by tissue scar after tissue cardiomyocyte after cardiomyocyte death. Myocardial death. Myocardialinfarction (MI) infarction occurs due(MI) tooccurs the prolonged due to the death prolonged of cardiomyocytes death of cardiomyocytes following a coronary following artery a coronaryocclusion. artery MI causes occlusion. a wound MI healing causes processa woun characterizedd healing process by excessive characterized inflammatory by excessive reactions inflammatoryand scarring [7 reactions]. Forming and an appropriatescarring [7]. replacement Forming an scar appropriate at the site ofreplacement infarction and scar cardiomyocytes at the site of infarctionnecrosis is and an essential cardiomyocytes response necrosis to maintaining is an essential the structure response of the to heartmaintaining and preventing the structure myocardial of the heartrupture. and Moreover, preventing di myocardialffuse fibrosis rupture. (also known Moreover, as reactive diffuse fibrosis) fibrosis (also occurs known when as the reactive affected fibrosis) area is occursreplaced when by scar the tissue affected after area cardiomyocytes is replaced death.by scar This tissue type after of fibrosis cardiomyocytes can be stimulated death. by This pro-fibrotic type of fibrosismediators can or be prolonged stimulated stress, by evenpro-fibrotic in the absencemediator ofs specificor prolonged cardiomyocyte stress, even death. in Conditionsthe absence that of specificapply constant cardiomyocyte pressure todeath. the heart, Conditions such as that aortic apply stenosis constant or systemic pressure hypertension, to the heart, have such been as shownaortic stenosisto increase or thesystemic wall stress hypertension, in the left have ventricle been and shown promote to increase reactive the fibrosis wall stress in the in chamber. the left ventricle and promotePathophysiological reactive fibrosis fluctuations in the chamber. that can trigger the inflammatory response of the heart, such as obesity,Pathophysiological diabetes, metabolic fluctuations syndrome, that heart can infections, trigger the and inflammatory drugs, cause response systemic of or the local heart, fibrosis such [as8]. obesity,Additionally, diabetes, invasive metabolic interstitial syndrome, fibrosis heart leads infections, to the and gradual drugs, deposition cause systemic of insoluble or local proteinsfibrosis [8].(amyloidosis) Additionally, or lipid invasive hyperglycosylation interstitial fibrosis (Anderson-Fabri’s leads to the disease)gradual indeposition the heart stroma of insoluble [9]. In aproteins normal (amyloidosis)heart, a well-defined or lipid fibroushyperglycosylation network helps (Anderson-Fabri’s to convert the function disease) of in individual the heart stroma cardiomyocytes [9]. In a normalinto an eheart,ffective a organwell-defined pump. fibrous However, network the ECM, helps which to convert is overproduced the function and of deposited individual in cardiomyocytespathological conditions, into an can effective interfere organ with thepump. normal However, electrical the conduction ECM, which pathway is overproduced between individual and depositedcardiomyocytes, in pathological which can conditions, adversely acanffect interfere the heart’s with contractile the normal performance. electrical conduction Additionally, pathway excess fibrous tissue in the heart affects the transfer of the power of individual cardiomyocytes to a powerful, Antioxidants 2020, 9, 1259 3 of 27 well-tuned pump function [10]. The accumulation of fibrous tissue around the coronary vessels in the heart’s small myocardium (i.e., perivascular fibrosis) can lead to localized micro ischemic sites, further impairing heart function [11]. Additionally, excessive collagen production in the ECM can affect diastolic function by impairing the elastic rebound of the myocardium as the myocardial cells relax. The accumulation of global or local ECM in the heart can lead to arrhythmia through reentry and other mechanisms [12]. 2.2. Mediators of Cardiac Fibrosis Increases in various circulatory hormones, cytokines and proteins due to stress or injury lead to fibroblast activation and differentiation and contribute to cardiac fibrosis [2]. Several studies have confirmed that various substances are involved in this process, suggesting that the renin-angiotensin system (RAS), transforming growth factor (TGF)-beta, endothelin (ET), and inflammation are key. Among them, inflammation will be the focus of the discussion [13]. To briefly explain factors other than inflammation, extensive pieces of evidence, based on various studies, link neurohormonal pathways to the pathogenesis of cardiac fibrosis.