1. Introduction: Atherosclerosis and inflammation
Atherosclerosis displays a wide spectrum of pathological clinical presentations. However, patients with atherosclerosis might be asymptomatic despite bearing atherosclerotic plaques for years or even decades within their vasculature. The initial presentation of atherosclerosis is shown by silent lesions that grow slowly and are termed “stable plaques” whereas the secondary clinical presentation is shown by overtly increased unstable plaques (Fuster, Badimon, Badimon & Chesebro, 1992).
Atheroma denotes the formation of adhering materials such as cholesterol, fat, and calcium within arteries (Lee & Libby, 1997). Clinical manifestations of atheroma typically include thrombosis in adults. The risk of developing thromboembolism and thrombosis as major complications of atherosclerosis is attributed to an atheroma’s instability rather than duration of the disease (Little et al., 1988). Furthermore, reactive oxygen species (ROS), hypoxia, and nitric oxide (NO) in expanding atheroma further accelerate proinflammatory responses and progression of atherosclerosis.
In all types of atherosclerotic plaques, inflammation constitutes a major component. Plaque rupture and thrombosis are accompanied by profound inflammatory infiltration (Van Der Wal, Becker, Van der Loos & Das, 1994). Among all stakeholders for inflammation, macrophages play a cardinal role, for example, in the pathogenesis of acute myocardial infarction (MI) at the cap rupture site. Ample evidence has revealed that T lymphocytes and activated macrophages usually triggers plaque destabilization (Hansson, 2005; Rocha & Libby, 2009). Improper assembly of macrophages and lymphocytes in plaques contributes to the generation and secretion of lytic enzymes and cytokines in fibrous cap, leading to rupture of the lesion, and ultimately, exacerbation of atherosclerosis (Hansson, 2005; Rocha & Libby, 2009).
With respect to inflammation in atherosclerosis, various strategies have displayed promises to cease secretion of inflammatory cytokine from macrophages and atherogenesis. One of the natural-occurring cellular defensive processes upon inflammatory insult is induction of mitophagy (Minton, 2016). Mitophagy refers to selective engulfment and removal of damaged/depolarized or superfluous mitochondria, thus preserving mitochondrial homeostasis (Ajoolabady et al., 2020; Ajoolabady, Aslkhodapasandhokmabad, Aghanejad, Zhang & Ren, 2020; Ajoolabady et al., 2021a; Ajoolabady et al., 2021b). Impairment of mitochondria triggers ROS generation, inflammasome activation, and cytokine secretion from macrophages (Ma et al., 2018). Recycling of damaged mitochondria by way of mitophagy retards inflammation in atherosclerotic lesions.
Melatonin is a commonly employed over-the-counter therapeutic agent with diverse biological activities, one of which is “mitophagy induction” (Zhou et al., 2018). Recent reports have delineated the role of melatonin in mitophagy regulation in many mammalian cells. Here we will decipher the role of melatonin in mitophagy regulation in macrophages based on the lessons acquired from mammalian cells. We wish to propose melatonin therapy as an adjuvant and alternative approach to cease inflammation in atherosclerotic lesions via macrophage mitophagy regulation. Our ultimate goal is to share perspectives on the accessory therapeutic strategies that accompany melatonin therapy, pharmaceutical, and natural mitophagy modulators as well as targeted delivery of melatonin and therapeutic agents to macrophages.