Metformin ameliorates TGF-β1–induced osteoblastic differentiation of human aortic valve interstitial cells by inhibiting β-catenin signaling

Liu, Fayuan; Chu, Chong; Wei, Qinyu; Shi, Jing; Li, Huadong; Dong, Nianguo

doi:10.1016/j.bbrc.2018.04.141

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…In addition, to further verify the role of TGF-β pathway in GACAT3mediated OA progression, the TGF-β downstream Smad proteins were evaluated in the presence of TGF-β1. TGF-β1 binds to TGF-β1 receptors to signal through the Smad proteins [46]. In the presence of TGF-β1, we found that miR-195 inhibited the activation of Smad proteins and translocate into the nucleus, while GACAT3 promoted the activation of Smad proteins.…”

Section: P R E P R I N Tmentioning

confidence: 79%

LncRNA GACAT3 contributes to osteoarthritis progression by suppressing growth and inducing apoptosis of chondrocytes through miR-195/TGF-β/Smad5 axis

Wang

Wei

et al. 2021

Arch Med Sci

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IntroductionLong non-coding RNAs (lncRNAs) were identified as an important regulator involved in the pathogenesis of osteoarthritis (OA). We aimed to evaluate whether lncRNA GACAT3 regulate OA progression by miR-195/TGF-β/Smad5 axis.Material and methodsExpression levels in tissue or chondrocytes were detected by RT-qPCR and Western blot. Effects of GACAT3 on cell viability, proliferation, apoptosis were evaluated. Targeted interactions of GACAT3, miR-195 and Smad5 were confirmed by dual luciferase reporter gene assay and biotin-coupled miRNA capture assay. Transfected or non-transfected cells were treated with TGF-β1 to verify role of TGF-β in mechanisms of OA progression.ResultsGACAT3 was overexpressed in OA tissues and associated with OA severity. After GACAT3 overexpression, the ability of cell viability and proliferation as well as proliferation-related genes was inhibited with enhanced level of apoptosis-related genes and Smad5. miR-195-5p was negatively targeted by GACAT3 and reversed effects caused by GACAT3. miR-195-5p negatively targeted Smad5. In the presence of TGF-β1, miR-195-5p mimics inhibited activation of Smad1/5, Smad5 and Smad2 compared with negative control. Immunofluorescence showed that miR-195-5p inhibited Smad1/5 activation and transfer to nucleus. In the presence of TGF-β1, GACAT3 facilitated the activation of TGF-β signaling. In clinical sample analysis, GACAT3 was positively correlated with Smad5 expression in OA patients.ConclusionsWe confirmed the up-regulation of GACAT3 in OA patients, and found that GACAT3 regulated the chondrocytes phenotypes by miR-195/TGF-β/Smad5 axis and in turn contributed to OA progression. Findings indicated that GACAT3 may act as a novel therapeutic target for controlling OA progression.

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Section: P R E P R I N Tmentioning

confidence: 79%

LncRNA GACAT3 contributes to osteoarthritis progression by suppressing growth and inducing apoptosis of chondrocytes through miR-195/TGF-β/Smad5 axis

Wang

Wei

et al. 2021

Arch Med Sci

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“…This is expected when there is no ligand (IL-38). Overexpression of IL-1R9 in mouse neurons and HEK293 cells selectively activates the c-Jun N-terminal kinase (JNK) signaling ( 51 , 52 ), a pathway that plays a role in AVIC pathobiology associated with CAVD progression ( 53 , 54 ). It is likely that elevated expression of IL-1R9 promotes JNK activation to contribute to enhanced inflammosteogenesis in AVICs.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

The

Graaf

Zhai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients’ CAVD valves compared to AVICs from non-CAVD valves. Recombinant IL-38 suppressed spontaneous inflammatory activity and calcium deposition in cultured AVICs. In mice, knockdown of IL-38 enhanced the production of inflammatory mediators in murine AVICs exposed to the proinflammatory stimulant matrilin-2. We also observed that in cultured AVICs matrilin-2 stimulation activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome with procaspase-1 cleavage into active caspase-1. The addition of IL-38 to matrilin-2–treated AVICs suppressed caspase-1 activation and reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, runt-related transcription factor 2, and alkaline phosphatase. Aged IL-38–deficient mice fed a high-fat diet exhibited aortic valve lesions compared to aged wild-type mice fed the same diet. The interleukin-1 receptor 9 (IL-1R9) is the putative receptor mediating the anti-inflammatory properties of IL-38; we observed that IL-1R9–deficient mice exhibited spontaneous aortic valve thickening and greater calcium deposition in AVICs compared to wild-type mice. These data demonstrate that IL-38 suppresses spontaneous and stimulated osteogenic activity in aortic valve via inhibition of the NLRP3 inflammasome and caspase-1. The findings of this study suggest that IL-38 has therapeutic potential for prevention of CAVD progression.

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“…Metformin can prevent the progression of atherosclerosis and the rupture of atherosclerotic plaques. CAVD has a pathological mechanism similar to atherosclerosis, and Liu et al indicated an inhibitory effect of metformin on the osteoblastic differentiation of AVICs induced by TGF-β1 by inhibiting β-catenin pathway; however, only few studies have reported the effectiveness of metformin on CAVD (Liu et al 2018 ). In this study, we revealed several novel findings.…”

Section: Discussionmentioning

confidence: 99%

Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in an AMPK dependent way

Qiao

Huang

Wang

et al. 2021

Mol Med

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Background Calcific aortic valve disease (CAVD) is the most prevalent valvular disease worldwide. However, no effective treatment could delay or prevent the progression of the disease due to the poor understanding of its pathological mechanism. Many studies showed that metformin exerted beneficial effects on multiple cardiovascular diseases by mediating multiple proteins such as AMPK, NF-κB, and AKT. This study aims to verify whether metformin can inhibit aortic calcification through the PI3K/AKT signaling pathway. Methods We first analyzed four microarray datasets to screen differentially expressed genes (DEGs) and signaling pathways related to CAVD. Then aortic valve samples were used to verify selected genes and pathways through immunohistochemistry (IHC) and western blot (WB) assays. Aortic valve interstitial cells (AVICs) were isolated from non-calcific aortic valves and then cultured with phosphate medium (PM) with or without metformin to verify whether metformin can inhibit the osteogenic differentiation and calcification of AVICs. Finally, we used inhibitors and siRNA targeting AMPK, NF-κB, and AKT to study the mechanism of metformin. Results We screened 227 DEGs; NF-κB and PI3K/AKT signaling pathways were implicated in the pathological mechanism of CAVD. IHC and WB experiments showed decreased AMPK and AKT and increased Bax in calcific aortic valves. PM treatment significantly reduced AMPK and PI3K/AKT signaling pathways, promoted Bax/Bcl2 ratio, and induced AVICs calcification. Metformin treatment ameliorated AVICs calcification and apoptosis by activating the PI3K/AKT signaling pathway. AMPK activation and NF-κB inhibition could inhibit AVICs calcification induced by PM treatment; however, AMPK and AKT inhibition reversed the protective effect of metformin. Conclusions This study, for the first time, demonstrates that metformin can inhibit AVICs in vitro calcification by activating the PI3K/AKT signaling pathway; this suggests that metformin may provide a potential target for the treatment of CAVD. And the PI3K/AKT signaling pathway emerges as an important regulatory axis in the pathological mechanism of CAVD.

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Metformin ameliorates TGF-β1–induced osteoblastic differentiation of human aortic valve interstitial cells by inhibiting β-catenin signaling

Cited by 14 publications

References 26 publications

LncRNA GACAT3 contributes to osteoarthritis progression by suppressing growth and inducing apoptosis of chondrocytes through miR-195/TGF-β/Smad5 axis

LncRNA GACAT3 contributes to osteoarthritis progression by suppressing growth and inducing apoptosis of chondrocytes through miR-195/TGF-β/Smad5 axis

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in an AMPK dependent way

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