Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities

Abstract

Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.

Fig. 1 |. Cellular events leading to the inception, progression and manifestation of cardiovascular events.

Top, Metabolic pathways upregulated in atheroresistant/stable disease areas are in blue, and pathways enriched in atheroprone/unstable disease areas are in red. Bottom, Circulating monocytes bind to adhesion molecules presented on the surface of activated ECs and transmigrate into the vessel wall. Monocytes then mature into macrophages and become foam cells, which can later become apoptotic due to uncontrolled uptake of modified LDL. In early atherosclerosis, these dead cells are efficiently cleared by macrophages. However, as atherosclerosis advances, the capacity for AC removal becomes impaired and promotes necrotic core formation. T cells similarly extravasate into the vessel wall and differentiate into subsets that influence the function of lesional cells. Upon a variety of atherogenic insults, medial vSMCs dedifferentiate and migrate towards the intima, where they initially assemble extracellular matrix in the fibrous cap. In addition, vSMCs can also derive from ECs that have undergone a mesenchymal transition. At later phases of atherosclerosis, vSMCs can adopt multiple cellular phenotypes that can destabilize the fibrous cap and drive the formation of rupture-prone atheromas.

Fig. 2 |. Metabolic pathways in lesional cells relevant to atherosclerosis.

Glucose is transported through the GLUT1 transporter and then proceeds down the glycolysis pathway. This pathway can give rise to lactate or feed into the TCA cycle. Pyruvate, a product of glycolysis, can enter the mitochondria through MPC1 or MPC2 and be converted to acetyl-CoA, which then enters the TCA cycle. Simultaneously, acyl-CoA can be transported into the mitochondria through the carnitine palmitoyltransferase (CPT) 1A and 2 enzymes and enter β-oxidation, generating acetyl-CoA that also feed into the TCA cycle. By-products of these pathways also fuel electron transport chain activity. Glutaminolysis occurs through the enzymes GLS1 and GLUD1, which generate α-ketoglutarate. Additionally, arginine can be converted into NO through the NOS enzymes (eNOS, nNOS or iNOS) or into the polyamine biosynthetic pathway, which also relies on methionine metabolism. Tryptophan is degraded by IDO1 into kynurenine and generates kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid or quinolinic acid. Serine is converted to glycine by SHMT1 or SHMT2 and gives rise the formation of the potent anti-oxidant GSH. GLUT1, glucose transporter 1; HK2, hexokinase 2; GPI, glucose-6-phosphate isomerase; PFKFB, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatases; PFK1, phosphofructokinase-1; TPI1, triosephosphate isomerase 1; ALDO, aldolase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PGK1, phosphoglycerate kinase 1; PGM1, phosphoglycerate mutase 1; ENO1, enolase 1; PKM, pyruvate kinase isozymes M1/M2; LDH, lactate dehydrogenase; MPC1/MPC2, mitochondrial pyruvate carriers 1 and 2; SHMT, serine hydroxymethyltransferase; IDO1, indoleamine 2,3-dioxygenase 1; ODC1, ornithine decarboxylase; SRM, spermidine synthase; SRM, spermine synthase; MAT2A, methionine adenosyltransferase 2A; AMD1, adenosylmethionine decarboxylase 1; GLUD1, glutamate dehydrogenase 1.

Fig. 3 |. Metabolic pathways in lesional cells and their consequences.

a, Unilaminar FSS induces the expression of transcription factors KLF2 and KLF4, which promote eNOS-mediated NO production, suppressing NF-κB activation and endothelial permeability. Mechanistically, FSS induces KLF2/KLF4 through the MEKK2/MEKK3–MEK5–ERK5 signalling cascade. FSS also decreases glycolysis in a KLF2-dependent manner, supporting mitochondrial metabolism, NADPH production and redox homeostasis. By contrast, disturbed FSS enhances glycolysis through HIF1α, contributing to EC activation. However, some reports indicate a complicated role for glycolysis in EC activation (dashed line). b, Growth factors and cytokines stimulate glucose uptake and promote glycolysis, resulting in dedifferentiation and phenotypic switching. Additionally, the PPP helps to maintain redox balance and inhibits apoptosis, which is counteracted by NOS-mediated NO. Alternatively, arginine metabolism into the polyamine biosynthetic pathway drives proliferation, migration and collagen deposition. IDO1-mediated kynurenine synthesis suppresses osteogenic reprogramming of vSMCs by stimulating the degradation of RUNX2, thereby restraining vascular calcification. c, Glycolysis stimulates pro-inflammatory cytokine secretion. However, lactate simultaneously drives a robust pro-resolving response—stimulating both IL-10 and continual efferocytosis. FAO prevents foam cell formation by suppressing CD36 expression and reducing foam cell formation. GSH synthesis drives continual efferocytosis and lowers superoxide levels. Efferotabolism of AC-derived cargo further stimulates continual efferocytosis, drives TGFβ production, and expands pro-resolving macrophages through the process known as ‘EIMP’. d, mTORC1-mediated glycolysis, serine metabolism into glycine and one-carbon units, and methionine-mediated histone methylation support the differentiation and expansion of T_eff cells. Additionally, cholesterol accumulation destabilizes T_reg cell differentiation and promotes T cell exhaustion and exT_reg cell expansion. OXPHOS stimulates AMPK-mediated repression of glycolysis and drives T_reg cell differentiation and stability. Cross-talk pathways driven by metabolites and soluble factors are shown in red.

Fig. 4 |. Current understanding of efferocytosis, the metabolism of AC-derived cargo and consequences thereof.

Binding of an AC to a macrophage activates cell-surface receptors that drive ERK1/ERK2 activation and DRP1-mediated mitochondrial fission. Free cholesterol from a degraded AC is either esterified by ACAT in the ER or exported by the cholesterol transporters ABCA1 and ABCG1. Methionine from a degraded AC is converted to SAM, which is used for DNA methylation that subsequently suppresses DUSP4 expression. This lifts repression of ERK1/ERK2 activation. ERK1/ERK2 signalling drives MYC expression, PGE2-mediated TGFβ production and AP1-mediated IL-10 secretion. AC-derived arginine is converted into putrescine and triggers cytoskeleton remodelling and continual efferocytosis. Recycling of AC-derived nucleotides mediates EIMP through a DNA-PK–mTORC2 signalling cascade. Fatty acids derived from ACs are used for FAO that promotes NAD⁺–SIRT1–PBX1 signalling that drives IL-10 expression. Concurrently, GLUT1-mediated glucose uptake promotes glycolysis and lactate production. Lactate is secreted from the macrophage via MCT1 to prime a pro-resolving microenvironment. Guided by mitochondrial fission, lactate is utilized for histone lactylation, which drives an epigenetic programme that promotes ARG1 expression.