Smoke Condensate-Induced Vascular Senescence and SASP Are Attenuated by Dual mTORC1/2 Inhibition with Rapalink-1
Jinliang You1, Hongjun Liu1, Dilaware Khan1
1Department of Neurosurgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Abstract:
Cigarette smoking contributes to vascular aging through oxidative stress, inflammation, and extracellular matrix (ECM) remodeling. Cellular senescence has been recognized as an important mechanism linking tobacco exposure to vascular dysfunction, but effective pharmacological strategies targeting this process remain scarce. In this study, we examined whether Rapalink-1, a dual inhibitor of mechanistic target of rapamycin complex 1 and complex 2 (mTORC1 and mTORC2), modulates smoke condensate (SC)-induced senescence in vascular cells. Human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs) were exposed to SC with or without Rapalink-1. SC increased intracellular reactive oxygen species, induced DNA damage, and promoted senescence-associated changes, including increased senescence-associated β-galactosidase (SA-β-gal) activity, reduced Lamin B1, and elevated p21 expression. These effects were accompanied by increased expression of inflammatory and matrix-remodeling genes associated with the senescence-associated secretory phenotype (SASP). Rapalink-1 co-treatment reduced oxidative stress and DNA damage, attenuated senescence markers, and partially normalized SASP-related and ECM-associated gene expression. Mechanistically, SC activated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling and increased downstream mTOR pathway activity, whereas Rapalink-1 dampened these signaling responses. Together, these findings indicate that dual mTORC1/2 inhibition by Rapalink-1 mitigates smoke condensate-induced senescence and inflammatory responses in vascular cells.
Insights
Rapalink-1, a dual mTOR inhibitor, reduces cellular senescence and inflammation in vascular cells caused by cigarette smoke. This finding offers a potential therapeutic strategy for smoking-related vascular aging.
Area of Science:
- Vascular Biology
- Cellular Aging
- Pharmacology
Background:
- Cigarette smoking accelerates vascular aging via oxidative stress, inflammation, and ECM remodeling.
- Cellular senescence is a key mechanism in tobacco-induced vascular dysfunction, with limited pharmacological interventions.
- The mechanistic target of rapamycin (mTOR) pathway plays a role in cellular senescence.
Purpose of the Study:
- To investigate if Rapalink-1, a dual inhibitor of mTOR complex 1 and 2 (mTORC1/2), can mitigate smoke condensate (SC)-induced senescence in vascular cells.
- To explore the effects of Rapalink-1 on oxidative stress, DNA damage, senescence markers, and inflammatory responses in SC-exposed cells.
- To elucidate the underlying molecular mechanisms, including NF-κB, MAPK, and mTOR signaling pathways.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs) were treated with SC, with or without Rapalink-1.
- Assessed SC-induced changes including reactive oxygen species, DNA damage, senescence-associated β-galactosidase (SA-β-gal) activity, Lamin B1, and p21 expression.
- Analyzed gene expression related to the senescence-associated secretory phenotype (SASP) and ECM remodeling, and evaluated NF-κB, MAPK, and mTOR signaling activation.
Main Results:
- SC exposure increased oxidative stress, DNA damage, and senescence markers (SA-β-gal, p21; decreased Lamin B1) in vascular cells.
- SC also upregulated inflammatory and ECM-remodeling genes associated with SASP, alongside activating NF-κB, MAPK, and mTOR signaling.
- Rapalink-1 co-treatment attenuated SC-induced oxidative stress and DNA damage, reduced senescence markers, partially normalized SASP and ECM gene expression, and inhibited key signaling pathways.
Conclusions:
- Dual mTORC1/2 inhibition by Rapalink-1 effectively mitigates smoke condensate-induced cellular senescence in vascular endothelial cells and smooth muscle cells.
- Rapalink-1 demonstrates potential as a therapeutic agent to counteract smoking-related vascular aging and inflammation.
- The study highlights the role of mTOR signaling in mediating the detrimental effects of cigarette smoke on vascular cells.
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