Celastrol attenuates arterial and valvular calcification via inhibiting BMP2/Smad1/5 signalling

Su, Zhongping; Zong, Pengyu; Chen, Ji; Yang, Shuo; Shen, Yun-Dun; Lü, Yan; Yang, Chuanxi; Kong, Xiangqing; Sheng, Yu; Sun, Wei

doi:10.1111/jcmm.15779

Cited by 19 publications

(13 citation statements)

References 43 publications

(81 reference statements)

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“…Recently, celastrol has also been shown to suppress Runx2 and OPN expression and reverse calcification in cultured porcine aortic VICs exposed to a medium containing high concentrations of calcium and phosphate. 301 Here, celastrol reverses calcium-induced up-regulation of BMP2‐BMPRII-Smad1/5 and Wnt/β‐catenin signalling pathways, preventing their respective nuclear translocation and modulation of osteogenic gene expression. These findings are replicated in vivo by intraperitoneal injection of celastrol in mice fed adenine to induce CKD and intraperitoneal vitamin D to induce valvular calcification.…”

Section: Targeting Ros In Cavdmentioning

confidence: 95%

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Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

Greenberg

Zhao

Shah

et al. 2021

Cardiovascular Research

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Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

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Section: Targeting Ros In Cavdmentioning

confidence: 95%

“…These findings are replicated in vivo by intraperitoneal injection of celastrol in mice fed adenine to induce CKD and intraperitoneal vitamin D to induce valvular calcification. 301 However, NOX2 involvement in this model of CAVD remains to be investigated. 301 …”

Section: Targeting Ros In Cavdmentioning

confidence: 96%

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

Greenberg

Zhao

Shah

et al. 2021

Cardiovascular Research

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“…Normal RVSMCs from passages three to five were used for subsequent experiments. RVSMCs were cultured in calcification medium containing 1.5 mM calcium and 2 mM phosphate for 3 days to induce calcification as described previously ( 13 , 14 ). For PLG treated groups, 2.5 μM PLG was added into medium or calcification medium and cells were cultured for 3 days.…”

Section: Methodsmentioning

confidence: 99%

Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling

Shi

et al. 2021

Front. Cardiovasc. Med.

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Vascular calcification frequently occurs in the process of chronic kidney disease, atherosclerosis and aging, resulting in an increased prevalence of cardiovascular events. Piperlongumine (PLG) is a natural product isolated from Piper longum L. Here, we aimed to explore the effect of PLG in high calcium- and phosphate-induced vascular calcification and the associated mechanism. Flow cytometry assays showed that PLG at concentrations <10 μM did not promote vascular smooth muscle cells (VSMCs) apoptosis, and PLG at concentrations >2.5 μM inhibited VSMCs proliferation. Thus, 2.5 μM PLG was selected for subsequent experiments. Alizarin red staining and ALP activity assays showed that PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN, as determined by qRT-PCR and western blotting. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs. PLG may act as a promising herbal extract for the clinical management of vascular calcification.

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“…It is well known that BMP2, a member of the TGF-β superfamily, is involved in the fibrosis process in a variety of tissues and cells through the Smad signaling pathway ( Wang et al, 2012 ; Wang and Wu, 2018 ; Hong et al, 2020 ; Su et al, 2020 ). The protein expression of BMP2 was up-regulated in the kidney tissues of ADR-induced FSGS model, while the YSHS granule significantly decreased the expression of BMP2 in the ADR-induced FSGS model ( Figures 6A,B ), which was consistent with the expression trend of Bmp2 mRNA detected by Real-time PCR ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway

Tan

Si²,

Yu³

et al. 2022

Front. Pharmacol.

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Focal segmental glomerulosclerosis (FSGS) is a common clinical condition with manifestations of nephrotic syndrome and fibrosis of the glomeruli and interstitium. Yi-Shen-Hua-Shi (YSHS) granule has been shown to have a good effect in alleviating nephrotic syndrome (NS) in clinical and in animal models of FSGS, but whether it can alleviate renal fibrosis in FSGS and its mechanism and targets are not clear. In this study, we explored the anti-fibrotic effect and the targets of the YSHS granule in an adriamycin (ADR)-induced FSGS model and found that the YSHS granule significantly improved the renal function of ADR-induced FSGS model mice and also significantly reduced the deposition of collagen fibers and the expression of mesenchymal cell markers FN, vimentin, and α-SMA in the glomeruli of ADR-induced FSGS mice, suggesting that the YSHS granule inhibited the fibrosis of sclerotic glomeruli. Subsequently, a network pharmacology-based approach was used to identify the potential targets of the YSHS granule for the alleviation of glomerulosclerosis in FSGS, and the results showed that the YSHS granule down-regulated the expressions of BMP2, GSTA1, GATS3, BST1, and S100A9 and up-regulated the expressions of TTR and GATM in ADR-induced FSGS model mice. We also proved that the YSHS granule inhibited the fibrosis in the glomeruli of ADR-induced FSGS model mice through the suppression of the BMP2/Smad signaling pathway.

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Celastrol attenuates arterial and valvular calcification via inhibiting BMP2/Smad1/5 signalling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 19 publications

References 43 publications

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling

Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway

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