Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats

Mišúth, Svetozár; M, Uhrínová; Klimas, Ján; Vavrincova-Yaghi, Diana; Vavrinec, Peter

doi:10.1016/j.vph.2021.106855

Cited by 9 publications

(2 citation statements)

References 35 publications

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“…Despite its effectiveness, DOX’s clinical utility is limited due to its adverse cardiovascular effects. Others and we have previously demonstrated that DOX induces senescence in endothelial cells (ECs) ( Yang et al, 2015 ; Chen et al, 2021a ; Matacchione et al, 2021 ; Misuth et al, 2021 ; Abdelgawad et al, 2022a ), which may contribute to the deleterious outcomes associated with DOX. ECs play several important roles such as maintaining vascular tone, initiating angiogenesis, and acting as a barrier to molecules circulating in the blood, all of which are impaired when ECs become senescent ( Abdelgawad et al, 2022b ).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…A diminished relaxation of aorta SMCs in response to NO donor, sodium nitrate, was also found in rats treated with DOX. This effect coincided with an induction of cellular senescence, manifested by increased SA-β-Gal, p16, p27, IL-6, and IL-8 [ 244 ].…”

Section: Introduction or A Few Words About Cardiooncologymentioning

confidence: 99%

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

et al. 2023

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Oncologic patients are subjected to four major treatment types: surgery, radiotherapy, chemotherapy, and immunotherapy. All nonsurgical forms of cancer management are known to potentially violate the structural and functional integrity of the cardiovascular system. The prevalence and severity of cardiotoxicity and vascular abnormalities led to the emergence of a clinical subdiscipline, called cardiooncology. This relatively new, but rapidly expanding area of knowledge, primarily focuses on clinical observations linking the adverse effects of cancer therapy with deteriorated quality of life of cancer survivors and their increased morbidity and mortality. Cellular and molecular determinants of these relations are far less understood, mainly because of several unsolved paths and contradicting findings in the literature. In this article, we provide a comprehensive view of the cellular and molecular etiology of cardiooncology. We pay particular attention to various intracellular processes that arise in cardiomyocytes, vascular endothelial cells, and smooth muscle cells treated in experimentally-controlled conditions in vitro and in vivo with ionizing radiation and drugs representing diverse modes of anti-cancer activity.

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Anthracycline-induced cardiotoxicity and cell senescence: new therapeutic option?

Seara

Kasai-Brunswick

Nascimento

et al. 2022

Cell. Mol. Life Sci.

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Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats

Cited by 9 publications

References 35 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

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

Anthracycline-induced cardiotoxicity and cell senescence: new therapeutic option?

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