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1.
Curr Opin Lipidol ; 30(5): 395-400, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335332

RESUMO

PURPOSE OF REVIEW: The two major challenges in cardiovascular medicine are to refine risk prediction and to improve pharmacological prevention and treatment. The concept of innate immune memory, which is called trained immunity, has the potential to improve clinical practice in these regards. RECENT FINDINGS: Monocytes and macrophages have the capability to develop a long-term proinflammatory and proatherogenic phenotype after brief exposure to inflammatory stimuli, such as oxidized low-density lipoprotein particles. This innate immune memory develops because of rewiring of intracellular metabolic pathways and epigenetic reprogramming of histone modifications. The persistence of circulating hyperresponsive monocytes in vivo is explained by the fact that training occurs in myeloid progenitor cells in the bone marrow. Several recent studies reported the presence of monocytes with a trained immune phenotype in patients with established atherosclerosis, and in patients with an increased risk for atherosclerosis because of dyslipoproteinemia. SUMMARY: In monocytes and their bone marrow progenitors, metabolic and epigenetic reprogramming can induce trained immunity, which might contribute to the persistent nonresolving inflammation that characterizes atherosclerosis. These pathways offer exciting novel drug targets to improve the prevention and treatment of cardiovascular disease.

2.
Cell Metab ; 30(1): 1-2, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31204280

RESUMO

Individuals with elevated LDL-cholesterol levels have an increased risk for cardiovascular disease. Despite lipid lowering strategies, however, a significant cardiovascular risk remains. Bekkering et al. show that monocytes from patients with familial hypercholesterolemia have a trained immunity phenotype and that lipid lowering with statins does not revert this pro-inflammatory phenotype.

3.
Cardiovasc Res ; 115(9): 1416-1424, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050710

RESUMO

Atherosclerosis is characterized by a persistent, low-grade inflammation of the arterial wall. Monocytes and monocyte-derived macrophages play a pivotal role in the various stages of atherosclerosis. In the past few years, metabolic reprogramming has been identified as an important controller of myeloid cell activation status. In addition, metabolic and epigenetic reprogramming are key regulatory mechanisms of trained immunity, which denotes the non-specific innate immune memory that can develop after brief stimulation of monocytes with microbial or non-microbial stimuli. In this review, we build the case that metabolic reprogramming of monocytes and macrophages, and trained immunity in particular, contribute to the pathophysiology of atherosclerosis. We discuss the specific metabolic adaptations, including changes in glycolysis, oxidative phosphorylation, and cholesterol metabolism, that have been reported in atherogenic milieus in vitro and in vivo. In addition, we will focus on the role of these metabolic pathways in the development of trained immunity.

4.
Mol Med ; 25(1): 16, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046673

RESUMO

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes. METHODS: To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls. RESULTS: Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls. CONCLUSION: We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.

5.
Front Immunol ; 10: 791, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037071

RESUMO

Objectives: Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). Methods: A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, ß-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested. Results: ß-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. ß-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to ß-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1ß, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. RNASEq upon ß-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance. Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels.

6.
Cardiovasc Res ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31119285

RESUMO

AIMS: Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigated whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism. METHODS AND RESULTS: We exposed human monocytes to aldosterone for 24h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and restimulated with Toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after restimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. CONCLUSION: Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated upregulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease.

7.
Int J Food Sci Nutr ; 70(8): 1014-1019, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30969142

RESUMO

High sodium intake increases cardiovascular risk by increasing blood pressure. The intake of coffee elevates blood pressure acutely. Preclinical evidence shows that this action of caffeine is enhanced by high salt intake. We hypothesised that high sodium intake augments the acute blood pressure response to coffee in humans. A randomised cross-over study (n = 15) was performed comparing the effect of lower (6 g/d; LS) with higher (12 g/d; HS) sodium chloride diet on blood pressure before and 2 h after regular coffee intake. Baseline blood pressure was 115 ± 4/84 ± 2/68 ± 1 during LS and 121 ± 4/89 ± 2/69 ± 1 mmHg during HS (SBP/Mean Arterial Pressure (MAP)/DBP; mean ± SE, p < 0.05 for SBP). During LS, blood pressure increased to 121 ± 4/91 ± 2/73 ± 1 (p < 0.05 for SBP, MAP, DBP versus baseline). HS did not significantly affect the impact of coffee on blood pressure (p > 0.3 for SBP, DBP; p > 0.05 for MAP). Sodium intake does not relevantly modulate the impact of regular coffee consumption on blood pressure.

8.
Circ Res ; 124(12): 1808-1820, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30971183

RESUMO

RATIONALE: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. OBJECTIVES: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. METHODS AND RESULTS: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk. CONCLUSIONS: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.

9.
Clin Sci (Lond) ; 133(2): 195-203, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30659160

RESUMO

Trained immunity is a recently described phenomenon whereby innate immune cells undergo functional reprogramming in response to microbial products, vaccines, or other stimuli, leading them to mount a sensitized nonspecific response to subsequent stimulation. While it is essential for the host response to pathogens, many diseases are the product of excessive or chronic inflammation. Atherosclerosis is a disease characterized by chronic low-grade inflammation of the arterial wall leading to plaque formation, where macrophages are the most abundant cell regulating plaque progression and stability. Recent studies have revealed a role for endogenous compounds related to atherosclerosis in the induction of trained immunity, which can enhance the expression of genes implicated in atherosclerosis and associated cardiovascular disease. Accelerated atherosclerosis remains the principal cause of morbidity and premature mortality in patients with diabetes, and the burden of vascular complications is greatly enhanced by prior periods of inadequate control of blood glucose. Recent findings suggest that long-term changes in bone marrow myeloid progenitors, similar to those induced by microbial products or high cholesterol diets in mice, may help to explain the chronic inflammatory state driving atherosclerosis and cardiovascular risk that exists for patients with diabetes despite improved metabolic control. From an immunometabolic perspective, we speculate that changes supporting the trained macrophage phenotype, such as up-regulation of glycolysis, indicate that a high glucose environment could enhance the pro-inflammatory consequences of trained immunity thereby contributing to the accelerated progression of atherosclerosis in patients with diabetes.

10.
Circulation ; 139(5): 636-646, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30586720

RESUMO

BACKGROUND: Despite successful restoration of epicardial vessel patency with primary percutaneous coronary intervention, coronary microvascular injury occurs in a large proportion of patients with ST-segment-elevation myocardial infarction, adversely affecting clinical and functional outcome. Ticagrelor has been reported to increase plasma adenosine levels, which might have a protective effect on the microcirculation. We investigated whether ticagrelor maintenance therapy after revascularized ST-segment-elevation myocardial infarction is associated with less coronary microvascular injury compared to prasugrel maintenance therapy. METHODS: A total of 110 patients with ST-segment-elevation myocardial infarction received a loading dose of ticagrelor and were randomized to maintenance therapy of ticagrelor (n=56) or prasugrel (n=54) after primary percutaneous coronary intervention. The primary outcome was coronary microvascular injury at 1 month, as determined with the index of microcirculatory resistance in the infarct-related artery. Cardiovascular magnetic resonance imaging was performed during the acute phase and at 1 month. RESULTS: The primary outcome of index of microcirculatory resistance was not superior in ticagrelor- or prasugrel-treated patients (ticagrelor, 21 [interquartile range, 15-39] U; prasugrel, 18 [interquartile range, 11-29] U; P=0.08). Recovery of microcirculatory resistance over time was not better in patients with ticagrelor versus prasugrel (ticagrelor, -13.9 U; prasugrel, -13.5 U; P=0.96). Intramyocardial hemorrhage was observed less frequently in patients receiving ticagrelor (23% versus 43%; P=0.04). At 1 month, no difference in infarct size was observed (ticagrelor, 7.6 [interquartile range, 3.7-14.4] g, prasugrel 9.9 [interquartile range, 5.7-16.6] g; P=0.17). The occurrence of microvascular obstruction was not different in patients on ticagrelor (28%) or prasugrel (41%; P=0.35). Plasma adenosine concentrations were not different during the index procedure and during maintenance therapy with ticagrelor or prasugrel. CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction, ticagrelor maintenance therapy was not superior to prasugrel in preventing coronary microvascular injury in the infarct-related territory as assessed by the index of microcirculatory resistance, and this resulted in a comparable infarct size at 1 month. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02422888.

11.
Expert Rev Neurother ; 19(2): 145-157, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30570362

RESUMO

INTRODUCTION: Parkinson's disease (PD) is a chronic multisystem disorder that causes a wide variety of motor and non-motor symptoms. Over time, the progressive nature of the disease increases the risk of complications such as falls and loss of independence, having a profound impact on quality of life. The complexity and heterogeneity of symptoms therefore warrant a holistic, multidisciplinary approach. Specific healthcare professionals, e.g. the movement disorders neurologist and the PD nurse specialist, are considered essential members of this multidisciplinary team. However, with our increasing knowledge about different aspects of the disease, other disciplines are also being recognized as important contributors to the healthcare team. Areas covered: The authors describe a selection of these relatively newly-recognized disciplines, including the specialist in vascular medicine, gastroenterologist, pulmonologist, neuro-ophthalmologist, urologist, geriatrician/elderly care physician, palliative care specialist and the dentist. Furthermore, they share the view of a person with PD on how patients and caregivers should be involved in the multidisciplinary team. Finally, they have included a perspective on the new role of the movement disorder neurologist, with care delivery via 'tele-neurology'. Expert commentary: Increased awareness about the potential role of these 'new' professionals will further improve disease management and quality of life of PD patients.

12.
Stroke ; 49(12): 2910-2917, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571420

RESUMO

Background and Purpose- Cerebral small vessel disease (cSVD) is the major vascular cause of cognitive decline and dementia. The pathogenesis of cSVD remains largely unknown, although several studies suggest a role for systemic inflammation. In certain pathophysiological situations, monocytes can reprogram toward a long-term proinflammatory phenotype, which has been termed trained immunity. We hypothesize that trained immunity contributes to the progression of cSVD. Methods- Individuals with mild-to-severe cSVD participated in the study. Severity of cSVD was determined by the white matter hyperintensities (WMH) volume (mL) on magnetic resonance imaging in 2006, 2015, and the progression between 2006 and 2015 (ΔWMH). Cytokine production was assessed after ex vivo stimulation of peripheral blood mononuclear cells and monocytes. Additionally, monocyte subsets were identified by flow cytometry. Results- Fifty-one subjects (70±6 years, 60% men, 5.1±6.4 mL ΔWMH) were included. Circulating hsIL (high-sensitivity interleukin)-6 correlated with cSVD ( P=0.005, rs=0.40). Cytokine production capacity by monocytes was associated with cSVD progression. Basal IL-8 and IL-17 production ( P=0.08, rs=0.25; P=0.03, rs=0.30) and IL-6 production after Pam3Cys stimulation in monocytes was associated with cSVD (n=35: P=0.008, rs=0.44). Conversely, interferon (IFN)-γ production in Candida albicans stimulated peripheral blood mononuclear cells was negatively correlated with cSVD ( P=0.009, rs=-0.36). Flow cytometry revealed a correlation of the intermediate monocyte subset with cSVD ( P=0.01, rs=0.36). Conclusions- Severity and progression of cSVD are not only correlated with systemic inflammation (hsIL-6) but also with trained immunity characteristics of circulating monocytes, in terms of an altered cytokine production capacity and a shift toward the proinflammatory intermediate monocyte subset.

13.
Diabetologia ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426168

RESUMO

AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Δ plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.

15.
Aging (Albany NY) ; 10(9): 2218-2219, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30215600
16.
Epigenomics ; 10(9): 1151-1154, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30238777
17.
EBioMedicine ; 33: 144-156, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29983349

RESUMO

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients.


Assuntos
Adenosina/metabolismo , Endotoxemia/imunologia , Hipóxia/imunologia , Interleucina-10/sangue , Adenosina/sangue , Animais , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/genética , Humanos , Hipóxia/sangue , Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Camundongos , Receptores Purinérgicos P1/metabolismo , Regulação para Cima
18.
Curr Opin Lipidol ; 29(5): 359-367, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30020200

RESUMO

PURPOSE OF REVIEW: It is increasingly recognized that profound metabolic changes occur in activated myeloid cells, which shape their inflammatory phenotype and cellular functions. The purpose of this review is to summarize the accumulating evidence that major metabolic adaptations occur in monocytes and macrophages in the context of atherosclerosis ultimately modulating atherosclerotic plaque formation. RECENT FINDINGS: Plaque macrophages show a profound metabolic reprogramming which is driven by atherogenic factors in the plaque microenvironment, such as damage associated molecular patterns, modified lipoproteins, and hypoxia. In addition, systemic atherogenic factors modulate metabolism of circulating monocytes and their bone marrow progenitors. Activation of glycolysis, the pentose phosphate pathway, and fatty acid synthesis, a reduction of fatty acid oxidation accompanied by complex changes in the lysosomal handling of lipids all appear to facilitate atherogenesis. These processes also drive the development of trained immunity, a phenomenon describing the persistent pro-inflammatory phenotype that develops after brief stimulation of monocytes with pro-atherogenic stimuli. SUMMARY: A pro-atherosclerotic environment reprograms the metabolism of myeloid cells in the various developmental phases of atherosclerosis. Knowledge of these metabolic programs facilitates the development of novel drugs to prevent atherosclerotic cardiovascular disease.

20.
Cardiovasc Res ; 114(7): 944-953, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29668907

RESUMO

The mineralocorticoid receptor (MR) is a member of the nuclear receptor steroid-binding family. The classical MR ligand aldosterone controls electrolyte and fluid homeostasis after binding in renal epithelial cells. However, more recent evidence suggests that activation of extrarenal MRs by aldosterone negatively impacts cardiovascular health independent of its effects on blood pressure: high levels of aldosterone associate with an increased cardiovascular event rate, where MR antagonists exert beneficial effects on cardiovascular mortality. The most important cause for cardiovascular events is atherosclerosis that is currently considered a low-grade inflammatory disorder of the arterial wall. In this inflammatory process, the innate immune system plays a deciding role, with the monocyte-derived macrophage being the most abundant cell in the atherosclerotic plaque. Intriguingly, both monocytes and macrophages express the MR, and a growing body of evidence shows that these cells are skewed into a pro-inflammatory and pro-atherosclerotic phenotype via MR stimulation. In this review, we detail the current perspective on the role of the monocyte and macrophage MR in atherosclerosis development and provide a comprehensive framework of the effects of MR activation of the innate immune system that might drive the pro-atherosclerotic outcome.

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