Evidence accumulates suggesting that cellular metabolic alterations fuel and dictate the inflammatory state of cells. In this review, we provide an overview of the observed metabolic reprogramming in ...endothelial cells and innate immune cells upon interaction with modified lipoproteins, thereby contributing to the progression of atherosclerosis.
Inflammatory endothelial cells at sites exposed to disturbed flow patterns show increased glycolytic activity. Atherogenic factors further enhance these metabolic changes by upregulating the mitochondrial energy production and thereby facilitating increased energy expenditure. Metabolic alterations are pivotal for monocyte and macrophage function as well. Exposure to atherogenic particles such as oxidized phospholipids lead to a regulatory metabolic pro-inflammatory phenotype, mediated via Toll-like receptor (TLR) 2 and the transcription factor erythroid 2-related factor (Nrf) 2. Translational studies highlighted the importance of metabolic alterations, as atherosclerotic plaques in the carotid arteries showed an increased glycolytic signature.
Alterations in cellular metabolism play an important role in controlling and steering the inflammatory state of both endothelial cells and immune cells. Targeting glycolysis may therefore provide an interesting route to attenuate the progression of atherosclerosis.
BACKGROUND:Elevated lipoprotein(a) Lp(a) is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is ...the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.
METHODS:In vivo imaging techniques including magnetic resonance imaging, F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.
RESULTS:We show that subjects with elevated Lp(a) (108 mg/dL 50–195 mg/dL; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL 2–28 mg/dL; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).
CONCLUSIONS:These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.
CLINICAL TRIAL REGISTRATION:URLhttp://www.trialregister.nl. Unique identifierNTR5006 (VIPER Study).
Lipoprotein(a) Lp(a) is a causal and independent risk factor for cardiovascular disease (CVD). People with elevated Lp(a) are often prescribed statins as they also often show elevated low-density ...lipoprotein cholesterol (LDL-C) levels. While statins are well-established in lowering LDL-C, their effect on Lp(a) remains unclear. We evaluated the effect of statins compared to placebo on Lp(a) and the effects of different types and intensities of statin therapy on Lp(a).
We conducted a systematic review and meta-analysis of randomized trials with a statin and placebo arm. Medline and EMBASE were searched until August 2019. Quality assessment of studies was done using Cochrane risk-of-bias tool (RoB 2). Mean difference of absolute and percentage changes of Lp(a) in the statin vs. the placebo arms were pooled using a random-effects meta-analysis. We compared effects of different types and intensities of statin therapy using subgroup- and network meta-analyses. Certainty of the evidence was determined using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Overall, 39 studies (24 448 participants) were included. Mean differences (95% confidence interval) of absolute and percentage changes in the statin vs. the placebo arms were 1.1 mg/dL (0.5-1.6, P < 0.0001) and 0.1% (-3.6% to 4.0%, P = 0.95), respectively (moderate-certainty evidence). None of the types of statins changed Lp(a) significantly compared to placebo (very low- to high-certainty evidence), as well as intensities of statin therapy (low- to moderate-certainty evidence).
Statin therapy does not lead to clinically important differences in Lp(a) compared to placebo in patients at risk for CVD. Our findings suggest that in these patients, statin therapy will not change Lp(a)-associated CVD risk.
RATIONALE:Patients with elevated levels of lipoprotein(a) Lp(a) are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of ...a proinflammatory state.
OBJECTIVE:We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.
METHODS AND RESULTS:We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.
CONCLUSIONS:Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
OBJECTIVE—Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local ...and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).
APPROACH AND RESULTS—Arterial wall inflammation and bone marrow activity were measured using F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol3.26 2.07–5.71) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 0.27–0.40; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytesPatients with FD 92% 86–95, controls 76% 66–81, P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10–276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.
CONCLUSIONS—Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
It is now evident that elevated circulating levels of triglycerides in the non-fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature ...cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin-like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC-III appear to hold considerable promise.
Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors, as well as to inflammatory agents and ...adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase-controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio-temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions and increases endothelial monolayer resistance. Collectively, our data show the importance of spatio-temporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions in the maintenance of the endothelial barrier.
Cellular senescence is a state of irreversible cell cycle arrest that has important physiological functions. However, cellular senescence is also a hallmark of ageing and has been associated with ...several pathological conditions. A wide range of factors including genotoxic stress, mitogens and inflammatory cytokines can induce senescence. Phenotypically, senescent cells are characterised by short telomeres, an enlarged nuclear area and damaged genomic and mitochondrial DNA. Secretion of proinflammatory proteins, also known as the senescence-associated secretory phenotype, is a characteristic of senescent cells that is thought to be the main contributor to their disease-inducing properties. In the past decade, the role of cellular senescence in the development of non-alcoholic fatty liver disease (NAFLD) and its progression towards non-alcoholic steatohepatitis (NASH) has garnered significant interest. Until recently, it was suggested that hepatocyte cellular senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in fatty liver disease. However, recent work in rodents has suggested that senescence may be a causal factor in NAFLD development. Although causality is yet to be established in humans, current evidence suggests that targeting senescent cells has therapeutic potential for NAFLD. We aim to provide insights into the quality of the evidence supporting a causal role of cellular senescence in the development of NAFLD in rodents and humans. We will elaborate on key cellular and molecular features of senescence and discuss the efficacy and safety of novel senolytic drugs for the treatment or prevention of NAFLD.
Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality worldwide. While it is traditionally attributed to lipid accumulation in the vascular ...endothelium, recent research has shown that plaque inflammation is an important additional driver of atherogenesis. Though clinical outcome trials utilizing anti-inflammatory agents have proven promising in terms of reducing ASCVD risk, it is imperative to identify novel actionable targets that are more specific to atherosclerosis to mitigate adverse effects associated with systemic immune suppression. To that end, this review explores the contributions of various immune cells from the innate and adaptive immune system in promoting and mitigating atherosclerosis by integrating findings from experimental studies, high-throughput multi-omics technologies, and epidemiological research.
Lipoproteins are important regulators of hematopoietic stem and progenitor cell (HSPC) biology, predominantly affecting myelopoiesis. Since myeloid cells, including monocytes and macrophages, promote ...the inflammatory response that propagates atherosclerosis, it is of interest whether the atherogenic low-density lipoprotein (LDL)-like particle lipoprotein(a) Lp(a) contributes to atherogenesis via stimulating myelopoiesis.
To assess the effects of Lp(a)-priming on long-term HSPC behavior we transplanted BM of Lp(a) transgenic mice, that had been exposed to elevated levels of Lp(a), into lethally-irradiated C57Bl6 mice and hematopoietic reconstitution was analyzed. No differences in HSPC populations or circulating myeloid cells were detected ten weeks after transplantation. Likewise, in vitro stimulation of C57Bl6 BM cells for 24 h with Lp(a) did not affect colony formation, total cell numbers or myeloid populations 7 days later.
To assess the effects of elevated levels of Lp(a) on myelopoiesis, C57Bl6 bone marrow (BM) cells were stimulated with lp(a) for 24 h, and a marked increase in granulocyte-monocyte progenitors, pro-inflammatory Ly6high monocytes and macrophages was observed. Seven days of continuous exposure to Lp(a) increased colony formation and enhanced the formation of pro-inflammatory monocytes and macrophages. Antibody-mediated neutralization of oxidized phospholipids abolished the Lp(a)-induced effects on myelopoiesis.
Lp(a) enhances the production of inflammatory monocytes at the bone marrow level but does not induce cell-intrinsic long-term priming of HSPCs. Given the short-term and direct nature of this effect, we postulate that Lp(a)-lowering treatment has the capacity to rapidly revert this multi-level inflammatory response.
•Lp(a) does not induce intrinsic priming of hematopoietic stem and progenitor cells.•Lp(a) enhances the production of inflammatory monocytes at the bone marrow level.•Lp(a)-lowering treatment may rapidly revert this multi-level inflammatory response.
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