(–)-Epicatechin Modulates Mitochondrial Redox in Vascular Cell Models of Oxidative Stress

Keller, Amy C.; Hull, Sara E.; Elajaili, Hanan; Johnston, Aspen; Knaub, Leslie A.; Chun, Ji Hye; Walker, Lori A.; Nozik‐Grayck, Eva; Reusch, Jane E.B.

doi:10.1155/2020/6392629

Cited by 21 publications

(22 citation statements)

References 44 publications

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“…ROS levels were regulated by the mitochondria-targeted redox cycler MitoParaquat (MitoPQ). The data support a hormetic model, in which low levels of ROS are cardioprotective, while higher levels are cardiotoxic [65].…”

Section: Cardiovascular Diseases (Cvd)supporting

confidence: 70%

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Schirrmacher¹

2021

Biomedicines

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A dose-response relationship to stressors, according to the hormesis theory, is characterized by low-dose stimulation and high-dose inhibition. It is non-linear with a low-dose optimum. Stress responses by cells lead to adapted vitality and fitness. Physical stress can be exerted through heat, radiation, or physical exercise. Chemical stressors include reactive species from oxygen (ROS), nitrogen (RNS), and carbon (RCS), carcinogens, elements, such as lithium (Li) and silicon (Si), and metals, such as silver (Ag), cadmium (Cd), and lead (Pb). Anthropogenic chemicals are agrochemicals (phytotoxins, herbicides), industrial chemicals, and pharmaceuticals. Biochemical stress can be exerted through toxins, medical drugs (e.g., cytostatics, psychopharmaceuticals, non-steroidal inhibitors of inflammation), and through fasting (dietary restriction). Key-lock interactions between enzymes and substrates, antigens and antibodies, antigen-presenting cells, and cognate T cells are the basics of biology, biochemistry, and immunology. Their rules do not obey linear dose-response relationships. The review provides examples of biologic stressors: oncolytic viruses (e.g., immuno-virotherapy of cancer) and hormones (e.g., melatonin, stress hormones). Molecular mechanisms of cellular stress adaptation involve the protein quality control system (PQS) and homeostasis of proteasome, endoplasmic reticulum, and mitochondria. Important components are transcription factors (e.g., Nrf2), micro-RNAs, heat shock proteins, ionic calcium, and enzymes (e.g., glutathion redox enzymes, DNA methyltransferases, and DNA repair enzymes). Cellular growth control, intercellular communication, and resistance to stress from microbial infections involve growth factors, cytokines, chemokines, interferons, and their respective receptors. The effects of hormesis during evolution are multifarious: cell protection and survival, evolutionary flexibility, and epigenetic memory. According to the hormesis theory, this is true for the entire biosphere, e.g., archaia, bacteria, fungi, plants, and the animal kingdoms.

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Section: Cardiovascular Diseases (Cvd)supporting

confidence: 70%

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Schirrmacher¹

2021

Biomedicines

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“…Previous studies have attributed elevated NO bioavailability in the presence of EPI to increased phosphorylation of eNOS at Ser177 (Carnevale et al, 2014;Ramirez-Sanchez et al, 2010Ramírez-Sánchez et al, 2016). Given that we and others demonstrated unaltered eNOS phosphorylation in the presence of EPI (Keller et al, 2020), it is plausible that arginase inhibition is the potential mechanism by which EPI increases NO production in HUVECs (Schnorr et al, 2008).…”

Section: Epi Dose-dependently Modulates Rons Productionsupporting

confidence: 47%

“…However, in our studies AMPK phosphorylation was suppressed in the presence of EPI for up to 1 h and was without further impact for up to 24 h, compared with controls. Supporting these findings, 2 h EPI treatment (1 µM) did not affect the phosphorylation of AMPK in HUVECs (Keller et al, 2020). Although EPI is capable of augmenting AMPK activity in liver and muscle tissue, and several cell types (Murase et al, 2009;Papadimitriou et al, 2014;Si et al, 2011), it seems that AMPK activation is not responsible for the therapeutic actions of EPI in HUVECs in culture.…”

Section: Epi Rapidly and Transiently Activates Erk1/2 Signallingmentioning

confidence: 64%

“…Whilst the potential of EPI to enhance markers of mitochondrial biogenesis and antioxidant capacity seems promising, it is unclear whether this effect translates to enhanced respiratory function or altered ROS production of vascular endothelial cells. In-fact, one recent study reported no impact of EPI on mitochondrial respiration (Keller et al, 2020), but the authors demonstrated that EPI may lower mitochondrial ROS production of HUVECs in the presence of high glucose. The challenge remains to resolve whether EPI modulates ROS production and mitochondrial function of vascular endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

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(–)-Epicatechin alters reactive oxygen and nitrogen species production independent of mitochondrial respiration in human vascular endothelial cells

Sadler

Barlow

Draijer

et al. 2021

Preprint

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IntroductionVascular endothelial dysfunction is characterised by lowered nitric oxide (NO) bioavailability, which may be explained by increased production of reactive oxygen species (ROS), mitochondrial dysfunction and altered cell signalling. (-)-Epicatechin (EPI) has proven effective in the context of vascular endothelial dysfunction, but the underlying mechanisms associated with EPI’s effects remain unclear.Objective(s)Our aim was to investigate whether EPI impacts reactive oxygen and nitrogen species (RONS) production and mitochondrial function of human vascular endothelial cells (HUVECs). We hypothesised that EPI would attenuate ROS production, increase NO bioavailability, and enhance indices of mitochondrial function.MethodsHUVECs were treated with EPI (0-20 μM) for up to 48 h. Mitochondrial and cellular ROS were measured in the absence and presence of antimycin A (AA), an inhibitor of the mitochondrial electron transport protein complex III, favouring ROS production. Genes associated with mitochondrial remodelling and the antioxidant response were quantified by RT-qPCR. Mitochondrial bioenergetics were assessed by respirometry and signalling responses determined by western blotting.ResultsMitochondrial superoxide production without AA was increased 32% and decreased 53% after 5 and 10 μM EPI treatment vs. CTRL (P<0.001). With AA, only 10 μM EPI increased mitochondrial superoxide production vs. CTRL (25%, P<0.001). NO bioavailability was increased by 45% with 10 μM EPI vs. CTRL (P=0.010). However, EPI did not impact mitochondrial respiration. NRF2 mRNA expression was increased 1.5- and 1.6-fold with 5 and 10 μM EPI over 48 h vs. CTRL (P=0.015 and P=0.001, respectively). Finally, EPI transiently enhanced ERK1/2 phosphorylation (2.9 and 3.2-fold over 15 min and 1 h vs. 0 h, respectively; P=0.035 and P=0.011).Conclusion(s)EPI dose dependently alters RONS production of HUVECs but does not impact mitochondrial respiration. The induction of NRF2 mRNA expression with EPI might relate to enhanced ERK1/2 signalling, rather than RONS production. In humans, EPI may improve vascular endothelial dysfunction via alteration of RONS and activation of cell signalling.

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“…− [ 31 , 32 ] and iii) decreasing mitochondrial O 2 . − production in vascular endothelial cells [ 67 ]. Additionally, EC was shown to inhibit other pathways associated with oxidant production, e.g.…”

Section: Flavonoids and Redox Biology In The Pathophysiology Of Disease: Evidence From Rodent Models And Cellsmentioning

confidence: 99%

Linking biomarkers of oxidative stress and disease with flavonoid consumption: From experimental models to humans

2021

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Identification of the links among flavonoid consumption, mitigation of oxidative stress and improvement of disease in humans has significantly advanced in the last decades. This review used (−)-epicatechin (EC) as an example of dietary flavonoids, and inflammation, endothelial dysfunction/hypertension and insulin resistance/diabetes as paradigms of human disease. In these pathologies, oxidative stress is part of their development and/or their perpetuation. Evidence from both, rodent studies and characterization of mechanisms in cell cultures are encouraging and mostly support indirect antioxidant actions of EC and EC metabolites in endothelial dysfunction and insulin resistance. Human studies also show beneficial effects of EC on these pathologies based on biomarkers of disease. However, there is limited available information on oxidative stress biomarkers and flavonoid consumption to allow establishing conclusive associations. The evolving discovery of metabolites that could serve as reliable markers of intake of specific flavonoids constitutes a powerful tool to link flavonoid consumption to disease and prevention of oxidative stress in human populations.

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(–)-Epicatechin Modulates Mitochondrial Redox in Vascular Cell Models of Oxidative Stress

Cited by 21 publications

References 44 publications

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

(–)-Epicatechin alters reactive oxygen and nitrogen species production independent of mitochondrial respiration in human vascular endothelial cells

Linking biomarkers of oxidative stress and disease with flavonoid consumption: From experimental models to humans

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