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A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.

ABSTRACT: Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are potentially harmful to the organism. Most of the senescence hallmarks were common for both RS and SIPS; however, some differences were observed. 32 % of doxorubicin-treated cells were arrested in the G2/M phase of the cell cycle, while 73 % of replicatively senescing cells were arrested in the G1 phase. Moreover, on the basis of alkaline phosphatase activity measurements, we show that a 7-day treatment with doxorubicin (dox), does not cause precocious cell calcification, which is a characteristic feature of RS. We did not observe calcification even though after 7 days of dox-treatment many other markers characteristic for senescent cells were present. It can suggest that dox-induced SIPS does not accelerate the mineralization of vessels. We consider that detailed characterization of the two types of cellular senescence can be useful in in vitro studies of potential anti-aging factors.

SUBMITTER: Bielak-Zmijewska A

PROVIDER: S-EPMC3905196 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.

Bielak-Zmijewska Anna A Wnuk Maciej M Przybylska Dorota D Grabowska Wioleta W Lewinska Anna A Alster Olga O Korwek Zbigniew Z Cmoch Anna A Myszka Aleksander A Pikula Slawomir S Mosieniak Grazyna G Sikora Ewa E

Biogerontology 20131116 1

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are p ...[more]

PMID: 24243065

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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.

Dataset Information

A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.

Publications

A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.

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