mTOR Inhibitor Rapalink-1 Prevents Ethanol-Induced Senescence in Endothelial Cells

Abstract

The cardiovascular risk factors, including smoking, ethanol, and oxidative stress, can induce cellular senescence. The senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase (MMPs). These pro-inflammatory molecules and MMPs promote the infiltration and accumulation of inflammatory cells in the vascular tissue, exacerbating vascular tissue inflammation. MMPs damage vascular tissue by degenerating the extracellular matrix. Consequently, these cellular and molecular events promote the initiation and progression of cardiovascular diseases. We used Rapalink-1, an mTOR inhibitor, to block ethanol-induced senescence. Rapalink-1 inhibited oxidative-stress-induced DNA damage and senescence in endothelial cells exposed to ethanol. It attenuated the relative protein expression of senescence marker P21 and improved the relative protein expression of DNA repair protein KU70 and aging marker Lamin B1. It inhibited the activation of NF-κB, MAPKs (P38 and ERK), and mTOR pathway proteins (mTOR, 4EBP-1, and S6). Moreover, Rapalink-1 suppressed ethanol-induced mRNA expression of ICAM-1, E-selectin, MCP-1, IL-8, MMP-2, and TIMP-2. Rapalink-1 also reduced the relative protein expression of MMP-2. In summary, Rapalink-1 prevented senescence, inhibited pro-inflammatory pathway activation, and ameliorated pro-inflammatory molecule expression and MMP-2.

Current Mouse Models of Intracranial Aneurysms: Analysis of Pharmacological Agents Used to Induce Aneurysms and Their Impact on Translational Research

“… 65 Therefore, in addition to shear stress, the proinflammatory and oxidative effect of angiotensin II and increased salt intake should be considered while investigating anti‐inflammatory interventions in a mouse model of the IAs. Moreover, angiotensin II and high salt promote endothelial dysfunction, 67 , 68 which consequently increases the expression of proinflammatory molecules and MMPs 69 , 70 , 71 , 72 that are known to contribute to IA pathophysiology 5 , 55 , 58 ; therefore, while using an animal model using angiotensin II or deoxycorticosterone to study endothelial dysfunction in IAs formation, the direct effect of angiotensin II and high salt on endothelial cells should be considered.…”

Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation

“…3 ). The expression of SASP factor is increased in endothelial cells as a consequence of stress induced premature senescence [ 26 , 27 , 38 , 39 ]. Colchicine mitigated the mRNA expression of the SASP factors induced by tobacco smoke condensate in endothelial cells (Fig.…”

“…5 ). It has already been reported that DNA damage, oxidative stress, and ethanol can activate these pathways [ 21 , 26 , 27 , 38 , 39 ]. Activation of these pathways has been linked to cellular senescence, and inhibiting these pathways could block cellular senescence [ 21 ].…”