Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis

Lin, Xiaoyan; Ouyang, Siyu; Zhi, Chenxi; Пин, Ли; Tan, Xiaoqian; Ma, Wentao; Yu, Jie-Ping; Peng, Tianhong; Chen, Xi; Liang, Li; Xie, Wei

doi:10.1016/j.abb.2021.109098

“…Apoptosis and autophagy influence the development and progression of atherosclerosis [ 19 ]. Of note, vascular smooth muscle cells (VSMCs) play an important role in foam cell formation, a hallmark of ASO [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans

Keqin

¹

,

Hou

²

,

Xu

³

et al. 2022

Cardiovascular Therapeutics

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Objective. Small heat shock protein-1 (HSPB1) is a small heat shock protein that participates in many cellular processes and alleviates stress-induced cell injury. Autophagy protects cells from many types of stress and plays a key role in preventing stress in arteriosclerosis obliterans (ASO). However, the roles of HSPB1 in autophagy and apoptosis in the context of ASO pathogenesis remain unclear. Methods. In vivo and in vitro studies were used to determine whether HSPB1 is associated with ASO progression. The expression of HSPB1 was measured in normal and sclerotic blood vessels. The role of HSPB1 and its potential downstream signaling pathway were determined in VSMCs by overexpressing and silencing HSPB1. Results. A total of 91 ASO patients admitted to and treated at our hospital from Sep. 2020 to Sep. 2021 were selected, and plasma HSPB1 expression was assessed. We divided the patients with ASO into the grade I ( n = 39 ), II ( n = 29 ), III ( n = 10 ), and IV ( n = 13 ) groups according to Fontaine’s classification. Plasma HSPB1 levels were markedly decreased in patients with grade III ( n = 10 ) and IV ( n = 13 ) ASO compared with patients with grade I ASO. Furthermore, HSPB1 expression was significantly decreased, and p62 and cleaved caspase-3 were increased in the sclerotic vasculature compared to the normal vasculature ( p < 0.05 ). Overexpression of HSPB1 promoted apoptosis of VSMCs following ox-LDL treatment. Knockdown of HSPB1 led to a marked increase in the expression of LC3II and Beclin-1 in ox-LDL-stimulated VSMCs, whereas knockdown of HSPB1 attenuated these changes ( p < 0.05 ). Importantly, overexpression of HSPB1 promoted the dephosphorylation of JNK in ox-LDL-stimulated VSMCs. Conversely, downregulation of HSPB1 induced the opposite change. Conclusion. Loss of HSPB1 promotes VSMC autophagy and inhibits VSMC apoptosis, which are associated with ASO. HSPB1 and its downstream signaling pathways could be potential therapeutic targets for ASO treatment.

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“…Sasaki et al showed that autophagy was significantly inhibited in chondrocytes of OA cartilage [ 31 ]. The SIRT1/FOXO1 pathway is important for regulating autophagy in vascular endothelial cells [ 32 ]. SIRT1/FOXO1 pathway-induced autophagy has been reported to facilitate the survival of energy-deficient cardiomyocytes [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol protection against IL-1β-induced chondrocyte damage via the SIRT1/FOXO1 signaling pathway

Liang

¹

,

Xing

²

,

Wang

³

et al. 2022

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Purpose Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration, synovial inflammation, osteophytes, and subchondral osteosclerosis. This study investigated the effects of resveratrol (RES) on extracellular matrix (ECM), autophagy, and apoptosis in OA pathogenesis via the SIRT1/FOXO1 pathway. Methods The microenvironment of OA chondrocytes was stimulated in vitro by adding 10 ng/mL of IL-1β to primary Wistar rat chondrocyte. Western blotting, immunofluorescence, quantitative real-time PCR, and transmission electron microscopy (TEM) were used for analysis. Results In the presence of IL-1β, RES increased the expression of silent information regulator (SIR) 1 protein and the phosphorylation level of forkhead transcription factor (FOXO) 1. It also promoted chondrocyte autophagy, increased the expression of SOX9 and aggrecan, inhibited chondrocyte apoptosis and matrix breakdown, and protected chondrocytes from IL-1β damage. After a SIRT1 inhibitor or FOXO1 inhibitor was added, the protective effect of RES on chondrocytes was significantly weakened. Our results suggest that RES regulates the ECM metabolism, autophagy, and apoptosis of OA chondrocytes through the SIRT1/FOXO1 pathway to ameliorate IL-1β-induced chondrocyte injury. Conclusion RES protects chondrocytes from IL-1β-induced damage by activating SIRT1/FOXO1 signaling and holds potential in OA treatment.

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“…Ferroptosis is characterized by the toxic lipid hydroperoxides induced by ROS, eventually leading to the redox disequilibrium, cellular antioxidant dysfunction, and irreparable oxidative damage. 46,47 Multiple signaling pathways as well as the cell organelles have also been found to involve in the ferroptosis regulation. 48 We and others 49−51 discerned that erastin could trigger death in HepG2 cells successfully.…”

Section: ■ Conclusionmentioning

confidence: 99%

G-Quadruplex Structures as a “Switch” Regulate ATF4 Expression in Ferroptotic HepG2 Cells

Liu

¹

,

Lian

²

,

Zhou

³

et al. 2023

ACS Chem. Biol.

3

0

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G-quadruplex (G4) is a noncanonical structure folded in a widespread manner by guanine-rich tandem repeated sequences. As a key response factor, activating transcription factor 4 (ATF4) has dual functions in managing iron-dependent ferroptosis by regulating amino acid synthesis and antioxidant-related gene expression. In our study, the activity of ATF4 expression was elevated in HepG2 cells induced by erastin. Based on preliminary bioinformatics analyses, the G-tract region, named WT, had high potential to form G4, and it was found that PDS could markedly weaken the increase of ATF4 expression by reducing the sensitivity of HepG2 cells toward erastin. In circular dichroism spectra, WT oligonucleotides showed characteristic molar ellipticity at specific wavelengths of parallel G4 structures, while corresponding single-base mutants possessed a weaker ability to form G4, which were consistent with immunostaining results. In addition, endogenous G4 formed by the WT motif was significantly destroyed in HepG2 cells treated with erastin. After being transfected with WT oligonucleotides, the levels of ATF4 mRNA decreased significantly regardless of being treated with erastin or not. Meanwhile, mutations of G-tracts could advantageously impact the luciferase expression downstream of an ATF4 promoter in reporter assays, manifesting that the decrease of endogenous G4 in the ATF4 promoter was positively associated with the expression enhanced by erastin in HepG2 cells.

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Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis

Cited by 79 publications

References 120 publications

HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans

HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans

Resveratrol protection against IL-1β-induced chondrocyte damage via the SIRT1/FOXO1 signaling pathway

G-Quadruplex Structures as a “Switch” Regulate ATF4 Expression in Ferroptotic HepG2 Cells

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