Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia

He, Yang; Cao, Xiaopei; Guo, Pujian; Li, Xiaochen; Shang, Huihui; Jin, Liu; Xie, Min; Xu, Yongjian; Liu, Xiansheng

doi:10.1016/j.freeradbiomed.2016.12.016

Cited by 58 publications

(38 citation statements)

References 37 publications

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“…Our group also demonstrated that quercetin exerted vasodilator effect in isolated pulmonary arteries, induced apoptosis and inhibited cell proliferation in PASMC [106]. The mechanism involved in the antiproliferative effects in both PASMC and endothelial cells seem to involve AKT [106,108,109], FOXO1-mTOR [110], and altered Bax/Bcl-2 ratio [108,111].…”

Section: Flavonoids and Other Polyphenolsmentioning

confidence: 74%

Impact of Nutrition on Pulmonary Arterial Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is characterized by sustained vasoconstriction, vascular remodeling, inflammation, and in situ thrombosis. Although there have been important advances in the knowledge of the pathophysiology of PAH, it remains a debilitating, limiting, and rapidly progressive disease. Vitamin D and iron deficiency are worldwide health problems of pandemic proportions. Notably, these nutritional alterations are largely more prevalent in PAH patients than in the general population and there are several pieces of evidence suggesting that they may trigger or aggravate disease progression. There are also several case reports associating scurvy, due to severe vitamin C deficiency, with PAH. Flavonoids such as quercetin, isoflavonoids such as genistein, and other dietary polyphenols including resveratrol slow the progression of the disease in animal models of PAH. Finally, the role of the gut microbiota and its interplay with the diet, host immune system, and energy metabolism is emerging in multiple cardiovascular diseases. The alteration of the gut microbiota has also been reported in animal models of PAH. It is thus possible that in the near future interventions targeting the nutritional status and the gut dysbiosis will improve the outcome of these patients.

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Section: Flavonoids and Other Polyphenolsmentioning

confidence: 74%

Impact of Nutrition on Pulmonary Arterial Hypertension

et al. 2020

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“…A number of publications have demonstrated that increased autophagy promotes the development of PAH and is involved in the development of the hyperproliferative/anti-apoptotic phenotype in PAEC and PASMC. As a note, this phenotype is a cellular signature of PAH pathogenesis [ 322 , 323 ]. In concordance with these findings, several autophagy inhibitors have been tested in animal models and were able to attenuate PAH development.…”

Section: Autophagy and Ros In Pulmonary Diseasesmentioning

confidence: 99%

“…And vice-versa, inhibition of AMPK or activation of mTOR pathway can inhibit autophagy and have a negative effect on PAH progression [ 323 , 325 ]. Interestingly, the dietary flavonoid quercetin, induces apoptosis and potentiates hypoxia-induced autophagy in PASMCs through a FoxO1-SENS3-mTOR pathway [ 322 , 326 ]. Furthermore, PASMCs treated with autophagic inhibitors are more susceptible to quercetin-induced apoptosis, suggesting that combining quercetin and autophagy inhibitors could be a novel therapeutic strategy for treating hypoxia-associated PH.…”

Section: Autophagy and Ros In Pulmonary Diseasesmentioning

confidence: 99%

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

et al. 2020

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The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy is a major cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of reactive oxygen species (ROS), leading to oxidative stress and the associated oxidative damage of cellular components. Accumulating evidence indicates that autophagy is necessary to maintain redox homeostasis. ROS activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular damaged macromolecules and dysfunctional organelles. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of autophagy. Current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. Altered autophagy phenotypes have been observed in lung diseases such as chronic obstructive lung disease, acute lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension, and asthma. Understanding the mechanisms by which ROS regulate autophagy will provide novel therapeutic targets for lung diseases. This review highlights our current understanding on the interplay between ROS and autophagy in the development of pulmonary disease.

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“…The activation of autophagy, which is involved in the proliferation and migration of PASMCs induced by hypoxia, was alleviated by treatment with the autophagy inhibitor 3-mA 41 . In addition, ATG5 siRNA could inhibit the proliferation of PASMCs by directly blocking autophagy 42 . Although a few studies have reported data on the role of autophagy in PASMCs, the specific molecular regulatory mechanism is not completely understood.…”

Section: Discussionmentioning

confidence: 98%

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs

Wei

Zhang

et al. 2020

Cell Death Dis

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Abnormal functional changes in pulmonary artery smooth muscle cells are the main causes of many lung diseases. Among, autophagy plays a crucial role. However, the specific molecular regulatory mechanism of autophagy in PASMCs remains unclear. Here, we first demonstrate that BCAT1 played a key role in the autophagy of hypoxic PASMCs and hypoxic model rats. BCAT1-induced activation and accumulation of the autophagy signaling proteins BECN1 and Atg5 by the endoplasmic reticulum (ER) stress pathway. Interestingly, we discovered that BCAT1 bound IRE1 on the ER to activate expression of its downstream pathway XBP-1-RIDD axis to activate autophagy. More importantly, we identified an RNA-binding protein, zinc finger protein 423, which promoted autophagy by binding adenylate/uridylate (AU)-rich elements in the BCAT1 mRNA 3′-untranslated region. Overall, our results identify BCAT1 as a potential therapeutic target for the clinical treatment of lung diseases and reveal a novel posttranscriptional regulatory mechanism and signaling pathway in hypoxia-induced PASMC autophagy.

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Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia

Cited by 58 publications

References 37 publications

Impact of Nutrition on Pulmonary Arterial Hypertension

Impact of Nutrition on Pulmonary Arterial Hypertension

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs

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