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.