The interaction between SD and immune disorders is bidirectional, with SD triggering an inflammatory response. In 2015, Carroll et al. [65] conducted a cross-sectional study of 70 volunteers, showed that PSD increased the production of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Animal studies [66-68] have also shown that the levels of pro-inflammatory cytokines and markers in SD rats significantly increased. During acute SD, inflammation activated through the complementary C3a-C3aR and C5a-C5aR pathways. Phagocytes in the peripheral circulation, such as monocytes and neutrophils increased, while IL-6 and C-reactive protein also increased. Production of circulating naive T cells and pro-inflammatory cytokines, such as IL-12, peaks at night, while production of cytotoxic effector leukocytes and anti-inflammatory cytokine IL-10 peaks during the day. Therefore, the circadian system and sleep work together to evoke a unique endocrine mechanism that effectively induces changes in white blood cell count and conversion to pro-inflammatory type 1 cytokines during nocturnal sleep [69].

In 2019, Said et al. [70] and De Lorenzo et al. [71], through examination of multiple models, showed that chronic SD may lead to changes in the balance of TH1-related chemokines, resulting in dysfunction in the distribution of circulating white blood cells, affecting neutrophil phagocytosis and nicotinamide adenine dinucleotide phosphate oxidase activity, leading to decreased CD4+ and CD8+ T cells in peripheral blood, and ultimately, resulting in immunosuppression. At the same time, diminished sleep duration leads to a decrease in the production of hypocretin (a neuropeptide that stimulates and promotes arousal) in the lateral hypothalamus. Additionally, SD results in an increase in the production of colony-stimulating factor-1 in hematopoietic cells. Colony-stimulating factor-1 induces the generation of macrophages and Ly-6C^high monocytes. These inflammatory cells induce atherosclerotic lesions [72]. Therefore, SD induces inflammatory responses and the release of inflammatory mediators [66-68]. Pro-inflammatory mediators and inflammatory cells play an essential role in myocardial injury by inducing atherosclerosis, MI, apoptosis, and reperfusion injury.

SD has a strong effect on lipid metabolism, which leads to atherosclerosis. In 2011, Kong et al. [73] published a cross-sectional study of a sample from Hong Kong, China. The study showed that children with long sleep duration had significantly reduced total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels compared with children with short sleep duration. Reduced sleep duration was also found to be associated with obesity and atherosclerotic dyslipidemia in young Hong Kong children. In 2019, Ness et al. [74] published a prospective study of 15 volunteers, and found that PSD for five days affected non-esterified fatty acid (NEFA) metabolism. A separate perspective cohort study [75] demonstrated a significant association between serum total NEFA concentration and the incidence of CHD mortality and non-fatal myocardial infarction.

In 2020, animal experiments conducted by Xing et al. [76] showed that after acute sleep deprivation 72 h in rats and mice, nuclear receptor subfamily 1 group D member 1-mediated inhibition of cholesterol 7α-hydroxylase can lead to elevated serum cholesterol level, hepatic cholesterol accumulation. At the same time, this may be related to the fact that sleep deprivation disrupted the secondary biological clock of mice [77]. It broke the rhythm of the inositol-requiring enzyme-1α pathway in the endoplasmic reticulum, and brought about incongruous expression levels of enzymes, which involved in fatty acid and cholesterol metabolism. Ultimately, the above mechanism caused impaired lipid metabolism. Long-term and uncontrolled exposure to hypercholesterolemia can lead to slowly progressive cardiovascular events [78]. In 2019, Wilms et al. [79] enrolled 15 healthy young men. They were assigned to three groups: regular sleep schedule (8 h), sleep restriction (4 h), and sleep deprivation (no sleep at all). The results showed that acute sleep deprivation leaded to profound remodelling of the transcriptomes of white adipose tissue (WAT), resulting in increased carbohydrate turnover and impaired glucose homeostasis. There are robust rhythms throughout WAT as well as subcutaneous adipose stem cells. These factors are connected with circadian rhythmic neuroendocrine hormones, such as growth hormone and glucocorticoids, both of which are known to affect the function and quality of adipose tissue [80]. Sleep deprivation causes hormonal changes, and there are complicated relationship between subtle hormonal changes and lipid metabolism disorders.

Many studies have shown that SD can aggravate myocardial ischemia-reperfusion injury by increasing energy consumption, decreasing antioxidant capacity, increasing oxygen free radical accumulation, and aggravating endoplasmic reticulum stress. Chronic circadian disruption usually activates the adaptive stress response. However, endoplasmic reticulum stress is the dominating catalyst of cell death in atherosclerosis. Figueiro et al. [81] found that GRP78/BiP, an endoplasmic reticulum chaperone for endoplasmic reticulum stress, was approximately 3 times higher in the macrophage-rich region of plaques for sleep-deprived mice than normal group. Arterial foam cells have a circadian rhythm response. Sleep deprivation can destroy the molecular clock of them and increase endoplasmic reticulum stress and apoptosis.

In 2005, Everson et al. [82] found catalase activity and glutathione content in the liver decreased by 23%–36% in rats subjected to five and ten days of SD, which continued or worsened with prolonged SD. Prospective studies involving volunteers by Trivedi et al. [83] and Jówko et al. [84] showed that after 24 h of acute SD, levels of glutathione, adenosine triphosphate (ATP), cysteine, and homocysteine decreased significantly, while activity of glutathione peroxidase and erythrocyte superoxide dismutase decreased, and the residual total antioxidant capacity in plasma increased.

Valvassori et al. [85], Rodrigues et al. [86], and Vosahlikova et al. [87], using acute sleep models, found that SD increased lipid peroxidation and DNA oxidative damage by down-regulating Na⁺/K⁺-ATPase activity, and caused changes in antioxidant enzymes in the frontal cortex, hippocampus, and serum, increased reactive oxygen species production, impaired mitochondrial biological ability, and affected mitochondrial activity, antioxidant defense enzyme, and caspase activity, which reduced oxidative phosphorylation and electron transport system respiration. In 2014, Qin and Deng [88], using a mouse model of SD lasting for seven days, found that SD increased inflammation and oxidative stress, and decreased the expression of cryptopigment-1 (CRY1) in vascular endothelial cells. Furthermore, the plaque area of the aortic sinus and the concentrations of TC, triglyceride, and LDL-C were also decreased in atherosclerotic mice by CRY1 overexpression. Overexpression of CYR1 relieves the development of atherosclerosis that may be associated with regulation of the toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) and cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway [88,89]. In 2020, Schilperoort et al. [90] observed increased expression of chemokine C-C motif ligand 2 (CCL2) protein in atherosclerotic lesions of mice, which exposed to alternating light and dark cycles. CCL2 is a chemokine that actively recruited monocytes to the site of endothelial injury. Inflammation and oxidative stress can induce CCL2 expression. CCL2-CCR2 axis plays an essential role in atherosclerosis. Therefore, oxidative stress and inflammation are the fundamental driving factors of endothelial dysfunction.

Vascular homeostasis and maintenance of endothelial function demonstrated functional rhythm oscillations synchronized with the 24-h diurnal cycle. Sleep disorders related to inflammation and sympathetic activation lead to a change in blood vessel architecture, characterized by elastic fiber fracture and disorder, an increase in inflammatory cells, lipid peroxidation, inflammation, and sympathetic activation, which may induce endothelial dysfunction. Endothelial dysfunction is a critical factor in the increased risk of CVD [91-95]. In models of acute and chronic SD in healthy volunteers, Sauvet et al. [96,97], Dettoni et al. [98], measured biomarkers of microvascular reactivity and endothelial activation, elevated plasma E-selectin levels, and significantly increased sympathetic neural activity during SD. Increased serum norepinephrine decreased endothelium-dependent venous dilatation, increased venous endothelial dysfunction, decreased endothelium-dependent vascular dilatation, and decreased local endothelial tolerance. Meanwhile, vascular dysfunction may precede and be independent of sympathetic nerve activity and systolic blood pressure increases. This suggests that endothelial dysfunction is not associated with blood pressure and sympathetic activity, but with inflammation and metabolic pathway responses.

More than 40% of protein-coding genes in human cells are controled by circadian clock gene, which showed tissue-specific circadian oscillations through clock-controlled transcription factors [99]. Many of these genes, which called CLOCK control genes (CCGs), played specific roles in regulating atherosclerosis of endothelial cells. Transcription factors brain-muscle-ARNT-like protein-2 (BMAL1) and CLOCK heterodimers combined with the promoter region of the period (PER1/2) and cryptochrome (CRY1/2) genes [100,101]. CLOCK/BMAL2 heterodimers integrated promoters of endothelial CCGs in the e-box enhancer region, such as plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin (TM) [102,103]. Both PAI-1 and TM are tightly associated with endothelial activation and the development of atherosclerotic plaques. Short sleep duration may exacerbate the instability of atherosclerosis and plaque by regulating CCGs expression in endothelial cells.

NO-mediated impairment of vasodilation contributes to atherosclerotic vascular disease and acute cardiovascular events. Prospective studies by Bain et al. [104], Sauvet et al. [105], and Stockelman et al. [106] showed that short sleep duration at night was associated with endothelium-dependent vasodilation dysfunction. This may be partly due to reduced bioavailability of NO, which leads to impaired vasodilation. At the same time, acetylcholine induces a decrease in vasodilation by increasing the concentration of pro-inflammatory cytokine TNF-α. endothelin-1 mediated increased vasoconstriction, resulting in increased pulse wave velocity, decreased vascular elasticity, and ultimately increased cardiovascular risk. In 2017, Jiang et al. [107] showed that the concentration of NO and cyclic guanosine phosphate (cGMP) and the phosphorylation level of endothelial NO synthase (eNOS) in the aorta decreased in rats subjected to five days of rapid movement SD. This suggests that SD can cause endothelial dysfunction and hypertension in middle-aged rats through the eNOS/NO/cGMP pathway.

Recent studies [108] have shown that chronic SD is associated with significantly reduced circulating levels of miRNA-125a, miRNA-126, and miRNA-146a. Dysregulation of these miRNAs may lead to increased inflammatory burden and endothelial dysfunction. miRNA-26a-5p induces the apoptosis of endothelial cells in CHD by inhibiting phosphatidyl inositol-3 kinase/protein kinase B pathway [109]. Acute SD alters methylation levels in healthy individuals [110]. These epigenomic changes may be used as biomarkers for sleep loss or as therapeutic targets for sleep-related diseases [111-114].