Naringenin ameliorates homocysteine induced endothelial damage via the AMPKα/Sirt1 pathway

Li, Hui; Liu, Linlin; Cao, Zhiwen; Li, Wen; Li, Rui; Chen, Youwen; Li, Chenxi; Song, Yurong; Liu, Guangzhi; Hu, Jing‐Hong; Liu, Zhenli; Lü, Cheng; Liu, Yuanyan

doi:10.1016/j.jare.2021.01.009

Cited by 31 publications

(16 citation statements)

References 32 publications

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“…EZH2 antagonism and SIRT1 agonism similarly increase NO production ( Gracia-Sancho et al, 2010 ; Kumar et al, 2013 ) and decrease EC activation ( Zhou et al, 2011 ; Wang J. et al, 2020 ) and EndMT ( Maleszewska et al, 2016 ; Liu Z.-H. et al, 2019 ) in experimental models of CVD ( Figure 2 ). More recently, natural antioxidants including epigallocatechin and naringenin have been shown to reduce oxidative damage in ECs via SIRT1 ( Li H. et al, 2021 ; Pai et al, 2021 ), and an intermittent fasting regimen was found to ameliorate vascular dysfunction in a murine model of diabetes by activating the SIRT1 pathway ( Hammer et al, 2021 ). Small molecule agents that target EZH2 and SIRT1 are currently available or under clinical study in several disease areas (e.g., oncology, dermatology, and nephrology) ( Ganesan et al, 2019 ; Fledderus et al, 2021 ), and may be investigated as potential anti-atherosclerotic agents by incorporating CVD endpoints into ongoing clinical trials.…”

Section: The Vascular Endothelium As An Emerging Therapeutic Target For Atherosclerosismentioning

confidence: 99%

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

2021

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Atherosclerosis, the chronic accumulation of cholesterol-rich plaque within arteries, is associated with a broad spectrum of cardiovascular diseases including myocardial infarction, aortic aneurysm, peripheral vascular disease, and stroke. Atherosclerotic cardiovascular disease remains a leading cause of mortality in high-income countries and recent years have witnessed a notable increase in prevalence within low- and middle-income regions of the world. Considering this prominent and evolving global burden, there is a need to identify the cellular mechanisms that underlie the pathogenesis of atherosclerosis to discover novel therapeutic targets for preventing or mitigating its clinical sequelae. Despite decades of research, we still do not fully understand the complex cell-cell interactions that drive atherosclerosis, but new investigative approaches are rapidly shedding light on these essential mechanisms. The vascular endothelium resides at the interface of systemic circulation and the underlying vessel wall and plays an essential role in governing pathophysiological processes during atherogenesis. In this review, we present emerging evidence that implicates the activated endothelium as a driver of atherosclerosis by directing site-specificity of plaque formation and by promoting plaque development through intracellular processes, which regulate endothelial cell proliferation and turnover, metabolism, permeability, and plasticity. Moreover, we highlight novel mechanisms of intercellular communication by which endothelial cells modulate the activity of key vascular cell populations involved in atherogenesis, and discuss how endothelial cells contribute to resolution biology – a process that is dysregulated in advanced plaques. Finally, we describe important future directions for preclinical atherosclerosis research, including epigenetic and targeted therapies, to limit the progression of atherosclerosis in at-risk or affected patients.

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Section: The Vascular Endothelium As An Emerging Therapeutic Target For Atherosclerosismentioning

confidence: 99%

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

2021

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“…Likewise, the Citrus flavonoids naringin and naringenin, the latter being the aglycone of naringin, are promising nutraceuticals in the strategy regarding the management of cardiovascular complications, improving the systolic pressure levels and the metabolic profile [ 3 ]. In vitro and in vivo evidence suggests that multiple pathways may be involved in these effects, including the positive modulation of the sirtuin 1 (SIRT1) enzyme pathway [ 4 , 5 , 6 ]. However, other putative mechanisms have been recognized in these biological actions, such as the stimulation of potassium channels, located both on sarcolemmal and on inner membranes of cardiac mitochondria, and the increase in bioavailability of nitric oxide, contributing to the preservation of the endothelial barrier at the vascular level [ 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective Effects of Grapefruit IntegroPectin Extracted via Hydrodynamic Cavitation from By-Products of Citrus Fruits Industry: Role of Mitochondrial Potassium Channels

Flori

Albanese²,

Calderone

et al. 2022

Foods

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Citrus flavonoids are well-known for their beneficial effects at the cardiovascular and cardio-metabolic level, but often the encouraging in vitro results are not confirmed by in vivo approaches; in addition, the clinical trials are also inconsistent. Their limited bioavailability can be, at least in part, the reason for these discrepancies. Therefore, many efforts have been made towards the improvement of their bioavailability. Hydrodynamic cavitation methods were successfully applied to the extraction of byproducts of the Citrus fruits industry, showing high process yields and affording stable phytocomplexes, known as IntegroPectin, endowed with great amounts of bioactive compounds and high water solubility. The cardioprotective effects of grapefruit IntegroPectin were evaluated by an ex vivo ischemia/reperfusion protocol. Further pharmacological characterization was carried out to assess the involvement of mitochondrial potassium channels. Grapefruit IntegroPectin, where naringin represented 98% of the flavonoids, showed anti-ischemic cardioprotective activity, which was better than pure naringenin (the bioactive aglycone of naringin). On cardiac-isolated mitochondria, this extract confirmed that naringenin/naringin were involved in the activation of mitochondrial potassium channels. The hydrodynamic cavitation-based extraction confirmed a valuable opportunity for the exploitation of Citrus fruits waste, with the end product presenting high levels of Citrus flavonoids and improved bioaccessibility that enhances its nutraceutical and economic value.

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“…It has been explored that deletion of AMPKα1 in VSMC inhibits Runx2 SUMOyalation thereby increasing Runx2 expression and promoting atherosclerotic calci cation in vivo (Cai et al 2016). Hcy can induce endothelial damage via the AMPKa/Sirt1 pathway (Li et al 2021). Furthermore, it was found that ERS could be inhibited by activating AMPK signalling (Hou et al 2019;Lu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

Xie

Shan

et al. 2023

Cell Biol Toxicol

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Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calci c aortic valve disease (CAVD).Background: The morbidity and mortality rates of calci c aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calci cation lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our ndings.Results: Herpud1 was highly expressed in calci ed human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) signi cantly attenuated aortic valve calci cation in high methionine diet-fed low-density lipoprotein receptor -/-(LDLR -/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis.Conclusions: These ndings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. HighlightsHomocysteine (hcy) promotes aortic valvular calci cation in vivo and in vitro.Herpud1 is upregulated in the lea ets of mice and humans with CAVD. Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of primary aortic valve interstitial cells (AVICs) induced by hcy. 4-Phenyl butyric acid, a compound that suppresses ERS and subsequent Herpud1 biosynthesis, signi cantly decreased AVIC calci cation in vitro after hcy stimulation and mitigated the severity of aortic valve brosis and calci cation in a murine model of CAVD.

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Naringenin ameliorates homocysteine induced endothelial damage via the AMPKα/Sirt1 pathway

Abstract: Graphical abstract

Cited by 31 publications

References 32 publications

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

Cardioprotective Effects of Grapefruit IntegroPectin Extracted via Hydrodynamic Cavitation from By-Products of Citrus Fruits Industry: Role of Mitochondrial Potassium Channels

Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

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