Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux

Tai, Shi; Sun, Jiaxing; Zhou, Yuying; Zhu, Zhaowei; He, Yuefeng; Chen, Mingxian; Yang, Hui; Xiao, Yichao; Tu, Tao; Tang, Liang; Li, Xuping; Zeng, Jianping; Zheng, Xi-Long; Zhou, Shenghua

doi:10.1016/j.jare.2021.12.009

Cited by 29 publications

(16 citation statements)

References 55 publications

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“… Venturini et al (2020) recently demonstrated through an in vitro model that SASP factors released due to DOX-induced endothelial senescence stimulate platelet activation and aggregation, which can contribute to atherothrombotic events. In agreement with the observed anti-inflammatory effect, metformin was previously shown to suppress the expression of SASP factors in RAS-induced senescent fibroblasts ( Moiseeva et al, 2013 ) and angiotensin-II-induced senescent vascular smooth muscle cells ( Tai et al, 2022 ). Moreover, a recent clinical study demonstrated that treatment with metformin was associated with a lower expression of SASP factors (IL-6 and TNF-α) in B cells isolated from elderly population ( Frasca et al, 2021 ).…”

Section: Discussionsupporting

confidence: 82%

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells

et al. 2023

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Introduction: Doxorubicin (DOX), a chemotherapeutic drug, induces senescence and increases the secretion of senescence-associated secretory phenotype (SASP) in endothelial cells (ECs), which contributes to DOX-induced inflammaging. Metformin, an anti-diabetic drug, demonstrates senomorphic effects on different models of senescence. However, the effects of metformin on DOX-induced endothelial senescence have not been reported before. Senescent ECs exhibit a hyper-inflammatory response to lipopolysachharide (LPS). Therefore, in our current work, we identified the effects of metformin on DOX-induced endothelial senescence and LPS-induced hyper-inflammation in senescent ECs.Methods: ECs were treated with DOX ± metformin for 24 h followed by 72 h incubation without DOX to establish senescence. Effects of metformin on senescence markers expression, SA-β-gal activity, and SASP secretion were assessed. To delineate the molecular mechanisms, the effects of metformin on major signaling pathways were determined. The effect of LPS ± metformin was determined by stimulating both senescent and non-senescent ECs with LPS for an additional 24 h.Results: Metformin corrected DOX-induced upregulation of senescence markers and decreased the secretion of SASP factors and adhesion molecules. These effects were associated with a significant inhibition of the JNK and NF-κB pathway. A significant hyper-inflammatory response to LPS was observed in DOX-induced senescent ECs compared to non-senescent ECs. Metformin blunted LPS-induced upregulation of pro-inflammatory SASP factors.Conclusion: Our study demonstrates that metformin mitigates DOX-induced endothelial senescence phenotype and ameliorates the hyper-inflammatory response to LPS. These findings suggest that metformin may protect against DOX-induced vascular aging and endothelial dysfunction and ameliorate infection-induced hyper-inflammation in DOX-treated cancer survivors.

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Section: Discussionsupporting

confidence: 82%

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells

et al. 2023

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“…Metformin has been reported to prevent cellular senescence in many types of cells such as fibroblasts [ 11 , 13 , 28 ], myoblasts [ 13 ], and vascular smooth muscle cells [ 17 ]. Mechanistically, the effect of metformin on senescence has been described to be at least through AMPKα [ 16 , 28 ], though other pathways such as autophagy [ 17 ], ROS [ 14 ], inflammation [ 11 ], or ER stress [ 13 ] have been involved. The role of leucine to target senescent cells is less understood [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, whole-body overexpression of the senescent marker, p21, in mice reduced muscle function and induced myofiber atrophy [8] suggesting a link between cellular senescence and muscle atrophy. Interestingly, metformin has been shown to protect against cellular senescence and the SASP in many different cell types [11][12][13][14][15][16][17], but is unexplored in mature skeletal muscle cells in conditions of muscle atrophy and when combined with leucine.…”

Section: Introductionmentioning

confidence: 99%

Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail

Petrocelli

Hart

Lang

et al. 2023

Aging

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Aging coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence-associated secretory phenotype, but the relationship of senescent cells to muscle atrophy is unclear. Previously, we found that a metformin + leucine (MET+LEU) treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the study's purpose was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during atrophy. Additionally, aged mouse single myofibers and older human donor primary myoblasts were individually isolated to determine the translational potential of MET+LEU on muscle cells. MET+LEU (25 + 125 µM) treatment increased myotube differentiation and prevented myotube atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent muscle atrophy and increase transcripts related to protein synthesis and decrease transcripts related to protein breakdown. Myotube atrophy resulted in dysregulated proteostasis that was reversed with MET+LEU and individually with proteasome inhibition (MG-132). Inflammatory and cellular senescence transcriptional pathways and respective transcripts were increased following myotube atrophy yet reversed with MET+LEU treatment. Dasatinib + quercetin (D+Q) senolytic prevented myotube atrophy similar to MET+LEU. Finally, MET+LEU prevented loss in myotube size in alternate in vitro models of muscle atrophy as well as in aged myofibers while, in human primary myotubes, MET+LEU prevented reductions in myonuclei fusion. These data support that MET+LEU has skeletal muscle cell-autonomous properties to prevent atrophy by reversing senescence and improving proteostasis.

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“…Numerous studies have shown that inhibition of autophagic flux can lead to vascular injury, for example by inhibiting the proliferative migration and contractile phenotype of HAVSMCs, as well as increasing vascular senescence and calcification [48][49][50] .…”

Section: Discussionmentioning

confidence: 99%

Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection

Cai¹,

Zhang

Lin

et al. 2023

Preprint

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Objective: Aortic dissection (AD) is a dangerous cardiovascular disease. However, its regulatory mechanism remains poorly understood. Autophagy is an important pathway for maintaining cellular homeostasis. Recent studies have shown that glycolysis and autophagy are essential for the development of AD. Elevated glycolysis can promote cells autophagy, but the relationship between the two is unclear. Enolase 2 (ENO2) is a glycolytic enzyme. Here, we investigated whether ENO2 can regulate autophagy in vascular smooth muscle cells (VSMCs) involved in the progression of AD. Approach and Results: The levels of ENO2 and autophagy-related proteins in aortic tissues from AD patients were identified by qRT-PCR, Western blot and IHC. We found that autophagosome clearance was impaired in aortic tissues and positively correlated with elevated ENO2 expression. Furthermore, aortic application of smooth muscle-specific adeno-associated virus (AAV) inhibiting ENO2 expression attenuated the development of AD in mice. in vitro experiments, downregulation of ENO2 partially restored PDGF-BB-induced impairment of autophagic flux, as evidenced by reduced expression of Beclin-1, SQSTM1, LC3BII/I and increased levels of LAMP2 in human aortic vascular smooth muscle cells (HAVSMCs). Similarly, increased levels of ENO2 exacerbated the autophagic dysfunction in HAVSMCs. Mechanistically, ENO2 may block autophagic flux through the ENO2-GAP43-ATF4 pathway and disrupt cellular homeostasis. Conclusion: Our data reveal a perturbing role of ENO2 in the homeostasis of VSMCs, suggesting ENO2 as a potential target for intervention in AD.

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Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux

Cited by 29 publications

References 55 publications

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells

Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail

Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection

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