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.