Role of sirtuins in attenuating plaque vulnerability in atherosclerosis

Abstract

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

Keywords: Atherosclerosis; Plaque formation; Plaque vulnerability; Sirtuins; Stable plaque; Unstable plaque.

Fig. 1

Inflammatory pathway leading to cascade resulting in plaque vulnerability and the effect of Sirtuins attenuating pro-inflammatory mediators. Intimal injury during vascular intervention or during atherogenesis induce release of DAMPs which stimulate inflammatory signaling by activating Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) leading to immune response involving increased recruitment of innate and adaptive immune cells, secretion of pro-inflammatory cytokines, and NLRP3 inflammasome activation. Altogether, they cause chronic inflammation in the plaque and induce vulnerability. Intimal injury also causes disruption of vasa-vasorum and leads to hypoxia and oxidative stress which in turn activate sirtuins. Increased sirtuins act as oxidative stress scavenger and reduce oxygen radicals and decrease oxidative stress which may lead to attenuated plaque vulnerability

Fig. 2

Pathological sequence of Ischemic events in the cardiovascular system resulting from vascular injuries and acute inflammation is gone awry. Oxidized Low-density Lipoprotein (oxLDL), NLR family pyrin domain containing 3 (NLRP3), Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-α (TNF-α), Interferon-γ (IFNγ)

Fig. 3

Pharmacological modulators to be used in sequential steps of development of atheromatous plaques. Angiotensin II (AngII), Oxidized Low-density Lipoprotein (oxLDL), NLR family pyrin domain containing 3 (NLRP3), Platelet-derived growth factor (PDGF), phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt), Monocyte chemoattractant protein-1 (MCP-1/CCL2), SRT (SIRT activator), 1,4 Dihydropyridine (DHP)