MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway

Zhang, Minghao; Li, Fan; Wang, Xiuyu; Gong, Jian Ping; Xian, Yushan; Wang, Guan; Zheng, Zihan; Shang, Chenxu; Wang, Bo; He, Yongqing; Wang, Weirong; Lin, Rong

doi:10.1007/s00418-020-01847-z

Cited by 45 publications

(33 citation statements)

References 29 publications

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“…Some microRNA (miRNA) can affect the development of atherosclerosis through PI3K signaling pathway, so miRNA may be candidate drugs for PI3K target drugs. MiR-145 can inhibit VSMC proliferation, migration and phenotypic transformation by blocking the activation of PI3K/Akt/mTOR signaling pathway (Zhang et al, 2020). However, miR-647 promotes the proliferation and migration of HA-VSMC treated with OX-LDL at least in part by targeting the PTEN/ PI3K/AKT pathway.…”

Section: Pi3k and Smcsmentioning

confidence: 99%

Role of PI3K in the Progression and Regression of Atherosclerosis

et al. 2021

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Phosphatidylinositol 3 kinase (PI3K) is a key molecule in the initiation of signal transduction pathways after the binding of extracellular signals to cell surface receptors. An intracellular kinase, PI3K activates multiple intracellular signaling pathways that affect cell growth, proliferation, migration, secretion, differentiation, transcription and translation. Dysregulation of PI3K activity, and as aberrant PI3K signaling, lead to a broad range of human diseases, such as cancer, immune disorders, diabetes, and cardiovascular diseases. A growing number of studies have shown that PI3K and its signaling pathways play key roles in the pathophysiological process of atherosclerosis. Furthermore, drugs targeting PI3K and its related signaling pathways are promising treatments for atherosclerosis. Therefore, we have reviewed how PI3K, an important regulatory factor, mediates the development of atherosclerosis and how targeting PI3K can be used to prevent and treat atherosclerosis.

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Section: Pi3k and Smcsmentioning

confidence: 99%

Role of PI3K in the Progression and Regression of Atherosclerosis

et al. 2021

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“…However, the regulation of the mTOR/p70S6K signaling pathway and its effects on the phenotypic switching of VSMCs in AMC is still poorly understood. In VSMCs, homocysteine‐induced proliferation, migration, and phenotypic transformation were reduced by overexpression of miR‐145 mediated via decreased PI3K, Akt, and mTOR expression 72 . Recently, a study showed that rapamycin treatment markedly declined the kaempferol‐induced osteogenetic activity associated with decreased RUNX2 and osterix expression involving mTOR, suggesting contribution of mTOR‐RUNX2/osterix signaling in osteogenic effect under in vitro and in vivo 73 .…”

Section: Discussionmentioning

confidence: 99%

Regulatory role of mammalian target of rapamycin signaling in exosome secretion and osteogenic changes in smooth muscle cells lacking acid ceramidase gene

et al. 2021

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Acid ceramidase (murine gene code: Asah1) (50 kDa) belongs to N‐terminal nucleophile hydrolase family. This enzyme is located in the lysosome, which mediates conversion of ceramide (CER) into sphingosine and free fatty acids at acidic pH. CER plays an important role in intracellular sphingolipid metabolism and its increase causes inflammation. The mammalian target of rapamycin complex 1 (mTORC1) signaling on late endosomes (LEs)/lysosomes may control cargo selection, membrane biogenesis, and exosome secretion, which may be fine controlled by lysosomal sphingolipids such as CER. This lysosomal‐CER‐mTOR signaling may be a crucial molecular mechanism responsible for development of arterial medial calcification (AMC). Torin‐1 (5 mg/kg/day), an mTOR inhibitor, significantly decreased aortic medial calcification accompanied with decreased expression of osteogenic markers like osteopontin (OSP) and runt‐related transcription factor 2 (RUNX2) and upregulation of smooth muscle 22α (SM22‐α) in mice receiving high dose of Vitamin D (500 000 IU/kg/day). Asah1fl/fl/SMCre mice had markedly increased co‐localization of mTORC1 with lysosome‐associated membrane protein‐1 (Lamp‐1) (lysosome marker) and decreased co‐localization of vacuolar protein sorting‐associated protein 16 (VPS16) (a multivesicular bodies [MVBs] marker) with Lamp‐1, suggesting mTOR activation caused reduced MVBs interaction with lysosomes. Torin‐1 significantly reduced the co‐localization of mTOR vs Lamp‐1, increased lysosome–MVB interaction which was associated with reduced accumulation of CD63 and annexin 2 (exosome markers) in the coronary arterial wall of mice. Using coronary artery smooth muscle cells (CASMCs), Pi‐stimulation significantly increased p‐mTOR expression in Asah1fl/fl/SMCre CASMCs as compared to WT/WT cells associated with increased calcium deposition and mineralization. Torin‐1 blocked Pi‐induced calcium deposition and mineralization. siRNA mTOR and Torin‐1 significantly reduce co‐localization of mTORC1 with Lamp‐1, increased VPS16 vs Lamp‐1 co‐localization in Pi‐stimulated CASMCs, associated with decreased exosome release. Functionally, Torin‐1 significantly reduces arterial stiffening as shown by restoration from increased pulse wave velocity and decreased elastin breaks. These results suggest that lysosomal CER‐mTOR signaling may play a critical role for the control of lysosome–MVB interaction, exosome secretion and arterial stiffening during AMC.

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“…As a catalytic subunit, mTOR can integrate various physiological stimuli to regulate the growth and metabolism of cells. The PI3K/Akt/mTOR signaling pathway is thought to be a crucial regulator of autophagy and apoptosis [55,56]. It has been con rmed that the mechanisms of apoptosis and autophagy in vascular smooth muscle cells were involved in vascular remodeling of hypertension [57].…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

Yao

Zhang

Yang

et al. 2020

Preprint

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Background: Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. Methods: In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin-eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. Results: After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change >1.3 and P-value <0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell aggregation. The cellular signaling pathways involved in glycosylation may be AGE-RAGE signaling pathway.Conclusion: The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE-RAGE signal pathway in glycation biology.

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MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway

Cited by 45 publications

References 29 publications

Role of PI3K in the Progression and Regression of Atherosclerosis

Role of PI3K in the Progression and Regression of Atherosclerosis

Regulatory role of mammalian target of rapamycin signaling in exosome secretion and osteogenic changes in smooth muscle cells lacking acid ceramidase gene

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

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