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Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.

ABSTRACT: Astragaloside IV (AS-IV), as one of the main active components of Astragalus membranaceus, has been reported to have cardiovascular protective effects. However, the role and molecular mechanism of AS-IV in vascular senescence have not been clearly stated. The in vitro aging model was constructed using bleomycin (BLM) in vascular smooth muscle cells (VSMCs). Cell senescence were assessed through Western blotting analysis of aging markers, flow cytometry, and the β-galactosidase (SA-β-Gal) kit. Mitophagy was determined through transmission electron microscopy, TMRM staining, and Western blotting analysis of p62. A model of aging blood vessels was induced by D-gal. The vascular wall thickness of mice was also evaluated by H&E staining. Our data proved that AS-IV plays an anti-senescent role in vitro and in vivo. Results showed that AS-IV effectively improved mitochondrial injury, raised MMP, and mediated mitophagy in BLM-induced senescent VSMCs and D-gal induced aging mice. Parkin expression strengthened AS-IV's anti-senescent function. In conclusions, AS-IV attenuated BLM-induced VSMC senescence via Parkin to regulate mitophagy. Therefore, AS-IV-mediated Parkin might be a latent therapeutic agent and target for VSMC senescence.

SUBMITTER: Li H

PROVIDER: S-EPMC9515037 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.

Li Huijun H Xu Jialin J Zhang Yanan Y Hong Lei L He Zhijian Z Zeng Zhiheng Z Zhang Li L

Human cell 20220804 6

Astragaloside IV (AS-IV), as one of the main active components of Astragalus membranaceus, has been reported to have cardiovascular protective effects. However, the role and molecular mechanism of AS-IV in vascular senescence have not been clearly stated. The in vitro aging model was constructed using bleomycin (BLM) in vascular smooth muscle cells (VSMCs). Cell senescence were assessed through Western blotting analysis of aging markers, flow cytometry, and the β-galactosidase (SA-β-Gal) kit. Mi ...[more]

PMID: 35925474

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Project description:BackgroundSenescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.MethodsLong culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP+)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers.ResultsWe found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP+-induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence.ConclusionsOur findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

Project description:Graphical abstract Our data suggest that metformin regulates the level of autophagosome-lysosome fusion leading to the upregulation of autophagic flux and significantly alleviates functional and structural changes associated with aging arteries, such as collagen accumulation and elastin damage. Metformin treatment also prevents a senescence-associated secretory phenotype (SASP) and improves the proliferation and migration of senescent VSMCs. Furthermore, disrupting the autophagosome-lysosome fusion abrogates the anti-senescence effects induced by metformin in VSMCs. Autophagy process is complex and involves multiple steps, it is unknown whether p62 mediated-selected autophagy seen in metformin treatment also contributes to activation of autophagic flux. Altogether, metformin, as an anti-aging drug, together with its novel role, as a regulator of autophagic flux, contributes to reduced senescence and SASP of VSMCs. Highlights • Metformin treatment improved functional and structural changes occur in aging arteries.• Metformin treatment prevented a senescence-associated secretory phenotype and improved the proliferation and migration of senescent VSMCs.• Reduced autophagic flux during cellular and vascular senescence was reversed by metformin.• Metformin enhances autophagy flux at the level of autophagosome-lysosome fusion via upregulating LAMP1. Introduction Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin’s impact on VSMC senescence is largely undefined. Objectives To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. Methods Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. Results Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin’s anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. Conclusions Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.

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Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.

Publications

Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.

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