Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation

Kang, Gyeoung Jin; Kim, Young Ho; Lee, Chang Hoon

doi:10.3390/antiox9121259

Cited by 19 publications

(18 citation statements)

References 206 publications

(247 reference statements)

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“…Once in the brain, DHA is esterified into membrane phospholipids, being released and converted to bioactive mediators during neurotransmission and following brain injury [ 77 ]. The antioxidant properties of DHA and its metabolites, resolvins, neuroprotectins and 4-hydroxy-2E-hexenal, are mediated by Nrf2 activation and involve upregulation of heme oxygenase 1 (HO-1) to protect the brain against ischemic damage [ [78] , [79] , [80] ]. Post-stroke administration of DHA is effective in reducing brain injury [ [81] , [82] , [83] ] and improving sensorimotor function [ 84 , 85 ].…”

Section: Protective Role Of Scfas Against Oxidative and Mitochondrial Stress Involving Keap1-nrf2 Signalingmentioning

confidence: 99%

Short-chain fatty acids as modulators of redox signaling in health and disease

et al. 2021

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Short-chain fatty acids (SCFAs), produced by colonic bacteria and obtained from the diet, have been linked to beneficial effects on human health associated with their metabolic and signaling properties. Their physiological functions are related to their aliphatic tail length and dependent on the activation of specific membrane receptors. In this review, we focus on the mechanisms underlying SCFAs mediated protection against oxidative and mitochondrial stress and their role in regulating metabolic pathways in specific tissues. We critically evaluate the evidence for their cytoprotective roles in suppressing inflammation and carcinogenesis and the consequences of aging. The ability of these natural compounds to induce signaling pathways, involving nuclear erythroid 2-related factor 2 (Nrf2), contributes to the maintenance of redox homeostasis under physiological conditions. SCFAs may thus serve as nutritional and therapeutic agents in healthy aging and in vascular and other diseases such as diabetes, neuropathologies and cancer.

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Section: Protective Role Of Scfas Against Oxidative and Mitochondrial Stress Involving Keap1-nrf2 Signalingmentioning

confidence: 99%

Short-chain fatty acids as modulators of redox signaling in health and disease

et al. 2021

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“…The nuclear factor erythropoietin 2 related factor 2 (NRF2) is involved in the process of controlling oxidative stress; due to its antioxidant activity, the NRF2 could protect the heart from the onset of cardiac fibrosis. Therefore, it is interesting that EPA, DHA, and some specialized pro-resolving lipid mediators (SPMs), such as resolvin D1 (RvD1), are capable of activating NRF2, demonstrating efficacy against cardiac fibrosis and therefore demonstrating effectiveness against HF and MI onset [ 73 ]. Furthermore, some mechanistic studies propose a different cardioprotective mechanism of n-3 PUFAs that involves their interaction with the free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor (GPR) for long-chain fatty acids.…”

Section: Heart Failure and Pufasmentioning

confidence: 99%

PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

et al. 2021

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Heart failure (HF) characterized by cardiac remodeling is a condition in which inflammation and fibrosis play a key role. Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) seems to produce good results. In fact, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and antioxidant properties and different cardioprotective mechanisms. In particular, following their interaction with the nuclear factor erythropoietin 2 related factor 2 (NRF2), the free fatty acid receptor 4 (Ffar4) receptor, or the G-protein coupled receptor 120 (GPR120) fibroblast receptors, they inhibit cardiac fibrosis and protect the heart from HF onset. Furthermore, n-3 PUFAs increase the left ventricular ejection fraction (LVEF), reduce global longitudinal deformation, E/e ratio (early ventricular filling and early mitral annulus velocity), soluble interleukin-1 receptor-like 1 (sST2) and high-sensitive C Reactive protein (hsCRP) levels, and increase flow-mediated dilation. Moreover, lower levels of brain natriuretic peptide (BNP) and serum norepinephrine (sNE) are reported and have a positive effect on cardiac hemodynamics. In addition, they reduce cardiac remodeling and inflammation by protecting patients from HF onset after myocardial infarction (MI). The positive effects of PUFA supplementation are associated with treatment duration and a daily dosage of 1–2 g. Therefore, both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) define dietary supplementation with n-3 PUFAs as an effective therapy for reducing the risk of hospitalization and death in HF patients. In this review, we seek to highlight the most recent studies related to the effect of PUFA supplementation in HF. For that purpose, a PubMed literature survey was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2015 to 2021.

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“…Therefore, we isolated and cultured the CFs from the neonatal mice hearts and explored the possible mechanism of FGF21 on inhibiting cardiac fibrosis. Oxidative stress is one of the causes of cardiac fibrosis in the injured heart [35]; we treated the CFs with H 2 O 2 to mimic the ischemic myocardium and detected the effect of FGF21 on the activation of TGF-β1-Smad2/3 signaling in the CFs. Western blotting results showed that compared with control, H 2 O 2 significantly increased the protein expression levels of TGF-β1, Smad2/3, MMP2 and MMP9 of CFs (all p < 0.01), which were inhibited by rhFGF21 intervention (all p < 0.01).…”

Section: Exercise Training Up-regulated Fgf21 Expression and Alleviated Cardiac Dysfunction And Cardiac Fibrosis In The Infarcted Heartmentioning

confidence: 99%

Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction

Kuang

et al. 2021

IJMS

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Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.

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Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation

Cited by 19 publications

References 206 publications

Short-chain fatty acids as modulators of redox signaling in health and disease

Short-chain fatty acids as modulators of redox signaling in health and disease

PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction

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