3 Recommendations for future atherosclerosis research
3.1 Mechanisms of lipid action
The retention of various lipoproteins(LDL,HDL,IDL,VLDL…) on the arterial wall is a necessary factor that causes oxidative immune stress, immune cell necrosis and accumulation, and then they leads to the formation of atherosclerosis. For example, lipoprotein lipase (LPL) and hepatic lipase convert plasma VLDL to intermediate low-density lipoprotein (IDL) and LDL particles high in cholesterol esters by hydrolysis of triglycerides (HL). LDL becomes more sensitive to oxidation and aggregation when it binds to proteoglycans, boosting foam cell production and proinflammatory reactions. In addition, OxLDL, which is converted from LDL by peroxidation, not only causes macrophages to release inflammatory cytokines and stimulate other inflammatory cell types, leading to macrophage death, but also induces many cellular responses in macrophages, dendritic cells, endothelial cells, T cells, and smooth muscle cells. Thus increases inflammation, lesion development, atherosclerosis, and unstable atherosclerotic plaques. Current and future obstacles include the need to characterize better the anti-atherosclerotic features of HDL in health and the pro-atherosclerotic impacts of HDL in illness to manage HDL activity better and possibly prevent and cure CVD. Interfering with the retention of apoB-containing lipoproteins in the artery wall is a possible atherosclerosis prevention method.
3.2 Immunometabolic mechanisms of macrophages
Smoking, hypertension, dyslipidemia, sedentary lifestyle, and diabetes are risk factors that impact the advancement of atherosclerosis(Santos et al., 2008). The significant residual cardiovascular risk persists after adequate medical treatment with antihypertensive and cholesterol-lowering medications such as statins. Targeting the inflammatory components of atherosclerosis and creating methods to modify the inflammatory phenotype of plaque macrophages are thus of significant interest. In a recent major clinical trial, the hopeful result that antibody-mediated IL-1 suppression lowers cardiovascular events in high-risk persons lends confidence to this strategy’s efficacy(McCulloch et al., 2019). The immunometabolic pathways that influence the inflammatory response of macrophages during atherosclerosis may represent the emergence of novel targets for therapeutic intervention.
3.3 Other mechanisms of immunometabolic action
Whether these pathways may represent new therapeutic intervention targets. M1 macrophages, Th1, and Th17 cells are often catabolic, whereas M2 macrophages and Treg are more anabolic(Zha et al., 2022). Apolipoprotein B lipoproteins are deposited in artery walls due to an imbalance in cellular and systemic cholesterol homeostasis(Sniderman et al., 2019). Under the effect of oxidative stress, it becomes pro-inflammatory and stimulates the migration of monocyte-derived cells into the subendothelial region. The transformation of monocytes into macrophages. Plaque macrophages absorb modified LDL, most of which become lipid-rich foam cells but can also be activated by lipoprotein-derived antigens, including phospholipids, cholesterol crystals, and apolipoprotein B peptides(de Graaf et al., 1991). In plaques, macrophages are exposed to oxidative stress and multiple pro-inflammatory cytokines(Cáceres et al., 2020), forming a complex microenvironment with metabolic reprogramming of glycolysis promotion and oxidative phosphorylation inhibition, releasing lipid content and other inflammatory debris to form a necrotic core, resulting in permanent macrophage inflammation, low-grade inflammation, and long-term plaque progression(Ip et al., 2017). This process’s critical metabolic processes include arginine metabolism, glycolysis, and oxidative phosphorylation (OXPHOS). First, the amino acid arginine metabolism is the basis for M1 and M2 classification. Second, inflammatory macrophages must swiftly discharge their inflammatory contents to rapidly supply energy and biosynthetic products(Aghasafari et al., 2019). In contrast, anti-inflammatory macrophages require a more stable energy source for a long-lasting repair response. Consequently, inflammatory macrophages demonstrate increased glucose absorption via the glucose transporter GLUT1 and accelerated aerobic glycolysis(Mattmiller et al., 2011), while oxidative phosphorylation via the TCA cycle is reduced. During this process, pyruvate, produced by the glycolytic pathway, is transformed into lactate, creating two ATP molecules and causing ROS(Olsen et al., 2013). Increasing the flux of glucose intermediates concurrently increases PPP, increasing NADPH synthesis, which is essential for cholesterol and fatty acid synthesis and required for phagocytosis and endoplasmic reticulum(Ying et al., 2021). High ratios of OXPHOS and FAO are a hallmark of anti-inflammatory macrophages.Both pyruvate and fatty acids enter the whole TCA cycle in the form of acetyl-CoA in these macrophages(Stacpoole, 2017), resulting in the continual synthesis of ATP via oxonate and the activation of genes involved in tissue healing. However, the significance of FAO in anti-inflammatory macrophage activity has recently been questioned because etomoxide-mediated FAO suppression or CPT2 impairment, an enzyme essential for fatty acid import, did not affect the M2 phenotype(Ma et al., 2018). It has also been established that the availability and metabolism of specific amino acids regulate innate immune cell responses. Glutathione can control macrophage IL-1β secretion, NO generation, and M2 polarization.Arginine metabolism is increased through the citrulline route and iNOS, leading to the generation of nitric oxide, which is related to the M1 phenotype(Early et al., 2018). Acetyl-CoA and S-adenosylmethionine can control epigenetic enzymes that acetylate and methylate histones through distinct pathways, thereby converting metabolic rearrangement into regulating gene expression and macrophage function(Su et al., 2016). In addition, the microenvironment of atherosclerotic plaques has a harmful impact on inhibitory Treg function. To improve immunological tolerance and homeostasis, Tregs dampen exaggerated inflammatory responses(Yuan et al., 2019b).This particular subpopulation of CD4+ T cells is characterized by constitutively high surface expression of the IL-2 receptor alpha chain (CD25)(Sakaguchi et al., 1995). Moreover, forkhead box protein 3 (Foxp3) is a lineage-specific marker and master regulator of Tregs. Tregs limit inflammatory responses by several methods, such as reduction of effector T cell proliferation, production of immunoregulatory cytokines such as IL-10 and transforming growth factor beta (TGFβ), and through cytotoxic T lymphocyte-associated protein 4 (CTLA-4) (APCs). Oxidative stress stimulates the synthesis of oxidized LDL particles, induces the proteasomal degradation of Foxp3, decreases OXPHOS in Treg, diminishes the suppressive Treg phenotype, and inhibits its activity CTRP6(Neupane et al., 2019). Further investigation of how the aforementioned metabolic mechanisms of macrophages and Treg cells are interrelated and combine to create an inflammatory response in atherosclerosis.