Melatonin as a treatment for atherosclerosis: focus on programmed cell death, inflammation and oxidative stress

Abstract

Delaying the development of atherosclerosis (AS) and decreasing cardiac ischemia-reperfusion damage remain serious challenges for the medical community. Chronic arterial disease, i.e., AS, is frequently linked to oxidative stress and inflammation as significant contributing causes. AS risk factors, such as hyperlipidemia, high blood pressure, age, hyperglycemia, smoking, high cholesterol, and irregular sleep patterns, can exacerbate AS in the carotid artery and further shrink its lumen. Finding new approaches that support plaque inhibition or stability is an ongoing problem. The last ten years have shown us that melatonin (MLT) affects the cardiovascular system, although its exact mechanisms of action are yet unknown. MLT's direct free radical scavenger activity, its indirect antioxidant qualities, and its anti-inflammatory capabilities all contribute to its atheroprotective effects on several pathogenic signaling pathways. Herein, we examine the evidence showing that MLT treatment has significant protective effects against AS and AS-related cardiovascular diseases. The numerous pieces of the puzzle that have been as for epigenetic and biogenetic targets for prevention and therapy against the atherosclerotic pathogenic processes are identified.

Keywords: Apoptosis; Atherosclerosis; Autophagy; Melatonin; Pyroptosis.

Fig. 1

This figure illustrates the two main apoptotic pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway. The intrinsic pathway is triggered by cellular stress, such as reactive oxygen species (ROS) and DNA damage, which activate p53, JNK, and pro-apoptotic proteins (BAX, BAD) while inhibiting Bcl-2, leading to mitochondrial membrane damage and cytochrome c (Cyt C) release. Cyt C binds Apaf-1, forming the apoptosome, which activates caspase-9 and executioner caspases (caspase-3, -6, -7), inducing apoptosis. The extrinsic pathway is initiated by the binding of Fas ligand (FasL) to Fas/TNFR, recruiting FADD and activating caspase-8, which directly triggers executioner caspases, leading to apoptos is. Both pathways ultimately result in controlled cell death through caspase activation

Fig. 2

This figure illustrates the molecular mechanisms linking oxidative stress and inflammation to atherosclerosis, as well as the protective effects of melatonin. Reactive oxygen species (ROS) generated by NADPH oxidase (NOX), mitochondria, and uncoupled endothelial nitric oxide synthase (eNOS) contribute to oxidative stress, leading to the activation of inflammatory pathways. Oxidized low-density lipoprotein (ox-LDL) and damage-associated molecular patterns (DAMPs) activate Toll-like receptor 4 (TLR4), which triggers nuclear factor kappa B (NF-κB) signaling. This results in the transcription of pro-inflammatory cytokines, promoting vascular inflammation and endothelial dysfunction. In parallel, oxidative stress and inflammatory stimuli activate the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, which in turn activates caspase-1, leading to the cleavage and release of pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). Additionally, caspase-1 promotes the expression of inducible nitric oxide synthase (iNOS) and adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and selectins, facilitating immune cell recruitment and plaque progression. Melatonin, a potent antioxidant and anti-inflammatory molecule, inhibits NF-κB activation and NLRP3 inflammasome assembly, thereby reducing cytokine production and endothelial dysfunction. This highlights its potential therapeutic role in mitigating oxidative stress and inflammation in atherosclerosis