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Published on: April 30, 2019
Olmesartan alleviates bleomycin-mediated vascular smooth muscle cell senescence via the miR-665/SDC1 axis
Yi Zhang1, Qingyang Liang1, Yanan Zhang2
1Department of Cardiology, The First Affiliated Hospital of Guangdong Pharmaceutical University Guangzhou 510080, Guangdong, China.
Abstract:
Olmesartan (OMST) is a new angiotensin II receptor antagonist recently approved by the FDA to treat cardiovascular diseases. We investigated the molecular mechanisms by which OMST regulates vascular senescence. In the present study, bleomycin (BLM) was used to induce senescence in vascular smooth muscle cells (VSMCs); after which, the cells were treated with OMST. The effects of OMST on BLM-mediated cell senescence were evaluated using cell adhesion, NAD+/NADH, and Annevin V/PI double staining assays, as well as by immunofluorescence staining of γH2AX, Edu flow cytometry, and evaluations of senescence-associated β-gal activity. Differentially expressed microRNAs (DEMs) were identified by miRNA microarray assays, and subsequently validated by quantitative real time PCR. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the miR-665 promoter. The target genes of miR-665 were predicted and confirmed using luciferase reporter assays. We found that miR-665 was upregulated in VSMCs in response to BLM-induced cellular senescence. BSP studies revealed that CpG sites in the promoter region of the miR-665 gene underwent extensive demethylation during BLM-induced cellular senescence, and there was a concomitant up-regulation of miR-665 expression. SDC1 mRNA was identified as a direct target of miR-665. Either miR-665 overexpression or SDC1 knockdown significantly reversed the effects of OMST on BLM-induced VSMC senescence. Moreover, SDC1 overexpression partially reversed the changes that occurred in cells with BLM-induced senescence caused by miR-665 overexpression. Our findings suggest that the miR-665/SDC1 axis functions as a vital modulator of VSMC senescence, and may represent a novel biological target for treating atherosclerosis.
Insights
Olmesartan (OMST) reverses vascular smooth muscle cell (VSMC) senescence by regulating the miR-665/SDC1 axis. This pathway, involving miR-665 upregulation and SDC1 demethylation, offers a novel therapeutic target for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Senescence
Background:
- Vascular senescence contributes to cardiovascular diseases.
- Olmesartan (OMST), an angiotensin II receptor antagonist, is used to treat cardiovascular conditions.
- The molecular mechanisms of OMST's regulation of vascular senescence are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which OMST regulates vascular senescence.
- To identify key molecular players involved in OMST's effects on vascular smooth muscle cells (VSMCs).
- To explore the potential of the miR-665/SDC1 axis as a therapeutic target for atherosclerosis.
Main Methods:
- Induction of VSMC senescence using bleomycin (BLM) and subsequent treatment with OMST.
- Evaluation of senescence using cell adhesion, NAD+/NADH assays, Annexin V/PI staining, γH2AX immunofluorescence, Edu flow cytometry, and senescence-associated β-gal activity.
- Identification and validation of differentially expressed microRNAs (DEMs) using miRNA microarray and quantitative real-time PCR.
- Analysis of miR-665 promoter methylation status using Bisulfite sequencing PCR (BSP).
- Confirmation of miR-665 target genes using luciferase reporter assays.
Main Results:
- Bleomycin-induced VSMC senescence led to upregulation of miR-665.
- Extensive demethylation of the miR-665 promoter correlated with increased miR-665 expression during senescence.
- SDC1 mRNA was identified as a direct target of miR-665.
- Overexpression of miR-665 or knockdown of SDC1 reversed OMST's effects on BLM-induced VSMC senescence.
- Overexpression of SDC1 partially reversed senescence changes induced by miR-665 overexpression.
Conclusions:
- The miR-665/SDC1 axis is a critical regulator of VSMC senescence.
- This axis represents a novel biological target for treating atherosclerosis.
- OMST exerts its protective effects, at least partly, through modulation of the miR-665/SDC1 pathway.
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