Bavachin Protects Human Aortic Smooth Muscle Cells Against β-Glycerophosphate-Mediated Vascular Calcification and Apoptosis via Activation of mTOR-Dependent Autophagy and Suppression of β-Catenin Signaling

He, Hongwu; Law, Betty Yuen Kwan; Ni, Zhaohui; Qiu, Congling; Qu, Yuan Qing; Wu, An-Guo; Han, Yu; Song, Qibin; Zheng, Wenlu; Liu, Yong; He, Yanzheng; Wong, Vincent Kam Wai

doi:10.3389/fphar.2019.01427

Cited by 32 publications

(16 citation statements)

References 49 publications

(52 reference statements)

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“…Bavachin suppresses apoptosis and calcification effects in HASMCs. Mechanism of the above hormonal effect is dependent on Atg7/mTOR-mediated autophagy pathway and suppression of Wnt/β-catenin signaling [ 60 ]. Cozzolino group also claimed the related role of autophagy and apoptosis in the iron citrate preventing calcium deposition in high Pi-calcified VSMC associated with an iron-induced positive modulation of GAS6/AXL synthesis.…”

Section: Autophagy Affects Vascular Calcification By Inhibiting Apoptosismentioning

confidence: 99%

“…In hyperphosphate-induced VC, inhibition of calcium aggradation can be attained by inhibiting apoptosis and potentiating autophagy and many hormonal molecules exhibits their critical roles [58][59][60][61]. Melatonin protected VSMCs against apoptosis and attenuated β-GP-induced VSMC calcification via autophagy stimulation associated to an AMPK/mTOR/ULK1 signaling pathway [59].…”

Section: Autophagy Inhibits Apoptosis and Vascular Calcificationmentioning

confidence: 99%

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Multiple functions of autophagy in vascular calcification

Zhou

Yuan

et al. 2021

Cell Biosci

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Background Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. Methods In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. Results Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification. Conclusion The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

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Section: Autophagy Affects Vascular Calcification By Inhibiting Apoptosismentioning

confidence: 99%

Section: Autophagy Inhibits Apoptosis and Vascular Calcificationmentioning

confidence: 99%

Multiple functions of autophagy in vascular calcification

Zhou

Yuan

et al. 2021

Cell Biosci

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“…Since Klotho knockout mice developed aggravated VCN, it was proposed that mTOR promotes VCN through suppression of Klotho [ 56 ]. Furthermore, the flavonoid bavachin ameliorated VCN by inhibiting mTOR, whereas wortmannin or Atg7 knockdown abrogated the protective effects of bavachin in vitro [ 57 ]. Lastly, HDAC1 was downregulated in VCN, while LSD1 was upregulated.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, mTOR overexpression has been shown to enhance VCN, while mTOR inhibition ameliorated VSMC calcification. Consequentially, rapamycin, adiponectin and bavachin have been shown to attenuate VCN due to their ability to inhibit mTOR activity [ 54 , 56 , 57 ]. Epigenetic regulation of mTOR activity has also been shown to modulate VCN.…”

Section: Discussionmentioning

confidence: 99%

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Neutel

Hendrickx

Martinet

et al. 2020

IJMS

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Background: Autophagy is a highly conserved catabolic homeostatic process, crucial for cell survival. It has been shown that autophagy can modulate different cardiovascular pathologies, including vascular calcification (VCN). Objective: To assess how modulation of autophagy, either through induction or inhibition, affects vascular and valvular calcification and to determine the therapeutic applicability of inducing autophagy. Data sources: A systematic review of English language articles using MEDLINE/PubMed, Web of Science (WoS) and the Cochrane library. The search terms included autophagy, autolysosome, mitophagy, endoplasmic reticulum (ER)-phagy, lysosomal, calcification and calcinosis. Study characteristics: Thirty-seven articles were selected based on pre-defined eligibility criteria. Thirty-three studies (89%) studied vascular smooth muscle cell (VSMC) calcification of which 27 (82%) studies investigated autophagy and six (18%) studies lysosomal function in VCN. Four studies (11%) studied aortic valve calcification (AVCN). Thirty-four studies were published in the time period 2015–2020 (92%). Conclusion: There is compelling evidence that both autophagy and lysosomal function are critical regulators of VCN, which opens new perspectives for treatment strategies. However, there are still challenges to overcome, such as the development of more selective pharmacological agents and standardization of methods to measure autophagic flux.

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“…Alternatively, analyses can be used to track cellular signaling molecules and downstream effects associated with environmental stimulation, especially to determine the dynamics of rapid responses. As the second messenger of cells, calcium is an important molecule that responds to environmental stimulation and is also related to the molecular function of OPN [ 34 ]. It has been reported that the application of soluble OPN or RGD peptides induced the transient elevation of [Ca 2+ ]i in human osteoclast-like cells isolated from giant cell tumor of bone [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels

Huang

Niu

et al. 2021

BMC Cancer

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Background Tumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication, however, the exact role and regulation of the OPN splicing isoforms was not well understood. Methods In this study, the effects of conditioned medium from the culture of OPN splicing isoforms overexpressing cells on cell functions were evaluated. The methods of nuclear calcium reporter assays and subcellular distribution of nuclear factor of activated T cells c2 (NFATc2) assays were used to investigate the molecular mechanism underlining the roles of OPN splicing isoforms. Results We found that the survival of NSCLC cells treated with cisplatin was increased by secretory OPNc in the condition medium, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent nuclear translocation of NFATc2. Conclusions The results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment.

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Bavachin Protects Human Aortic Smooth Muscle Cells Against β-Glycerophosphate-Mediated Vascular Calcification and Apoptosis via Activation of mTOR-Dependent Autophagy and Suppression of β-Catenin Signaling

Cited by 32 publications

References 49 publications

Multiple functions of autophagy in vascular calcification

Multiple functions of autophagy in vascular calcification

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels

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