Melatonin Alleviates Age-Associated Endothelial Injury of Atherosclerosis via Regulating Telomere Function

Abstract

Background Atherosclerosis is an aging-related disease, partly attributed to telomerase dysfunction. This study aims to investigate whether telomere dysfunction-related vascular aging is involved in the protection mechanism of melatonin (MLT) in atherosclerosis. Methods Young and aged ApoE −/− mice were used to establish atherosclerotic mice model. H&E staining and immunofluorescence assay were performed to detect endothelial cell injury and apoptosis. Inflammatory cytokines and oxidative stress-related factors were determined using corresponding commercial assay kits. Telomerase activity was detected by TRAP assay, and SA-β-gal staining was conducted to evaluate cellular senescence. HUVECs were treated with H 2 O 2 for 1 h to induce senescence. Western blot was performed to measure protein expression. Results An obvious vascular endothelial injury, reflected by excessive production of inflammatory cytokines, elevated ROS, MDA and SOD levels, and more apoptotic endothelial cells, was found in atherosclerotic mice, especially in aged mice, which were then greatly suppressed by MLT. In addition, telomere dysfunction and senescence occurred in atherosclerosis, especially in aged mice, while MLT significantly alleviated the conditions. CYP1A1, one of the targeted genes of MLT, was verified to be upregulated in atherosclerotic mice but downregulated by MLT. Furthermore, H 2 O 2 induced a senescence model in HUVECs, which was accompanied with a remarkably increased cell viability loss and apoptosis rate, and a downregulated telomerase activity of HUVECs, and this phenomenon was strengthened by RHPS4, an inhibitor of telomerase activity. However, MLT could partly abolish these changes in H 2 O 2 - and RHPS4-treated HUVECs, demonstrating that MLT alleviated vascular endothelial injury by regulating senescence and telomerase activity. Conclusions Collectively, this study provided evidence for the protective role of MLT in atherosclerosis through regulating telomere dysfunction-related vascular aging.

Pineal Gland from the Cell Culture to Animal Models: A Review

“…Telomeres function to promote cellular stability and replication and are, therefore, a widely accepted marker for endothelial cell dysfunction in the setting of atherosclerosis. Most notably, melatonin treatment reduced intimal thickening and endothelial apoptosis in the mouse model, further supporting melatonin’s beneficial cardiovascular properties [ 24 ].…”

“…Melatonin may also play a role in the inflammation [ 21 , 22 , 23 , 24 , 25 , 26 ]. Inflammation is part of the illness process, which is modulated by diverse compounds release by cells such as cytokines and interleukins.…”

“…Melatonin, the pineal gland’s major product, exerts anti-inflammatory, immunomodulatory, and anti-cancer effects on the human body. Melatonin production decreases with age, which suggests it may prove to be a useful target in the analysis of many age-related processes and disorders [ 24 , 25 , 26 ].…”

“…In a recent study, telomere dysfunction was associated with decreased melatonin production in elderly mice [ 24 ]. Telomeres function to promote cellular stability and replication and are, therefore, a widely accepted marker for endothelial cell dysfunction in the setting of atherosclerosis.…”

Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases

“…In this regard, it was proven that melatonin treatment prevented all the altered parameters related to aging at the cardiovascular level in an atherosclerotic aged-mouse model, such as increased ROS, malondialdehyde, and inflammatory cytokine levels, as well as cell apoptosis. Melatonin's ability to beneficially upregulate the activity of telomerase, explains its actions in preventing or attenuating cardiovascular dysfunction and exerting important anti-aging effects on the blood vessels (Xie et al, 2021). It has been widely documented that melatonin exerts its protective effect as a result of its antioxidant scavenging properties, its direct free radical detoxification, and its ability to preserve efficient oxygen metabolism in the mitochondria (Martinez-Cruz et al, 2002).…”