RESUMEN
Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.
Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Humanos , Ratones , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Colesterol , Inflamación/metabolismo , Leucocitos Mononucleares/metabolismo , Lípidos , Placa Aterosclerótica/tratamiento farmacológico , Succinatos/metabolismoAsunto(s)
Enfermedades Cardiovasculares , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Humanos , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/terapia , Productos Finales de Glicación Avanzada/metabolismoRESUMEN
Background and aims: In hyperglycemia, inflammation, oxidative stress and aging, Damage Associated Molecular Patterns (DAMPs) accumulate in conditions such as atherosclerosis. Binding of DAMPs to receptors such as the receptor for advanced glycation end products (RAGE) activates signal transduction cascades that contribute to cellular stress. The cytoplasmic domain (tail) of RAGE (ctRAGE) binds to the formin Diaphanous1 (DIAPH1), which is important for RAGE signaling. This Review will detail the evidence linking the RAGE/DIAPH1 signaling pathway to atherosclerosis and envisages future therapeutic opportunities from the "inside-out" point of view in affected cells. Methods: PubMed was searched using a variety of search terms, including "receptor for advanced glycation end products" along with various combinations including "and atherosclerosis," "soluble RAGE and atherosclerosis," "statins and RAGE," "PPAR and RAGE" and "SGLT2 inhibitor and RAGE." Results: In non-diabetic and diabetic mice, antagonism or global deletion of Ager (the gene encoding RAGE) retards progression and accelerates regression of atherosclerosis. Global deletion of Diaph1 in mice devoid of the low density lipoprotein receptor (Ldlr) significantly attenuates atherosclerosis; mice devoid of both Diaph1 and Ldlr display significantly lower plasma and liver concentrations of cholesterol and triglyceride compared to mice devoid of Ldlr. Associations between RAGE pathway and human atherosclerosis have been identified based on relationships between plasma/serum concentrations of RAGE ligands, soluble RAGEs and atherosclerosis. Conclusions: Efforts to target RAGE/DIAPH1 signaling through a small molecule antagonist therapeutic strategy hold promise to quell accelerated atherosclerosis in diabetes and in other forms of cardiovascular disease.
Asunto(s)
Aterosclerosis , Forminas , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Aterosclerosis/metabolismo , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Humanos , Forminas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , RatonesRESUMEN
Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic ß-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent ß-cell dysfunction and the potential residual risk of diabetes complications.