Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study

Li, Mengyu; Kwok, Man Ki; Fong, Shirley S.M.; Schooling, CM

doi:10.1038/s41598-019-44819-7

Cited by 21 publications

(12 citation statements)

References 63 publications

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“…Today, the immunomodulation of atherosclerosis is at the center of current research. Available data suggest that IDO regulation is mediated through various immunological signals (288), and also suggest that IDO is a promising therapeutic agent against atherosclerosis (284). Similarly, ARG inhibitors have been considered and evaluated as promising therapeutic agents against atherosclerosis and other CVDs since the 1990s (301,323).…”

Section: Resultsmentioning

confidence: 99%

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Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes

et al. 2020

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Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

“…Further to this, IDO deficiency dysregulates cytokine IL-10 release and promotes early-stage atherosclerosis ( 110 ). These data suggest that IDO, through its immune-inflammatory actions, may be a promising therapeutic agent against atherosclerosis ( 284 ).…”

Section: Immunomodulation Of Atherosclerosismentioning

confidence: 99%

Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes

et al. 2020

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“…A recent Mendelian randomization study found that IDO1 and KYAT3 inversely correlated with ischaemic heart disease (IHD), supporting the notion of a protective role for the kynurenine pathway against cardiovascular disease (CVD) in humans [15]. Interestingly, clinical studies have associated an increased L‐Kyn to Trp ratio (Kyn/Trp) in the plasma, which is used as a surrogate marker of IDO activity, with classic risk factors for CVD, such as body mass index and diabetes [16], as well as cardiovascular events [17‐19].…”

Section: Introductionmentioning

confidence: 92%

Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans

et al. 2020

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Background. The metabolism of tryptophan (Trp) along the kynurenine pathway has been shown to carry strong immunoregulatory properties. Several experimental studies indicate that this pathway is a major regulator of vascular inflammation and influences atherogenesis. Knowledge of the role of this pathway in human atherosclerosis remains incomplete. Objectives. In this study, we performed a multiplatform analysis of tissue samples, in vitro and in vivo functional assays to elucidate the potential role of the kynurenine pathway in human atherosclerosis. Methods and results. Comparison of transcriptomic data from carotid plaques and control arteries revealed an upregulation of enzymes within the quinolinic branch of the kynurenine pathway in the disease state, whilst the branch leading to the formation of kynurenic acid (KynA) was downregulated. Further analyses indicated that local inflammatory responses are closely tied to the deviation of the kynurenine pathway in the vascular wall. Analysis of cerebrovascular symptomatic and asymptomatic carotid stenosis data showed that the downregulation of KynA branch enzymes and reduced KynA production were associated with an increased probability of patients to undergo surgery due to an unstable disease. In vitro, we showed that KynA-mediated signalling through aryl hydrocarbon receptor (AhR) is a major regulator of human macrophage activation. Using a mouse model of peritoneal inflammation, we showed that KynA inhibits leukocyte recruitment. Conclusions. We have found that a deviation in the kynurenine pathway is associated with an increased probability of developing symptomatic unstable atherosclerotic disease. Our study suggests that KynA-mediated signalling through AhR is an important mechanism involved in the regulation of vascular inflammation.

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“…Mendelian randomization studies have now shown strong links between specific inflammatory proteins and lipid metabolism in patients with an inflammatory status, providing the impetus to develop novel systemic and vascular immunomodulatory approaches to address the public health challenge of cardiovascular disease (CVD). Thus, genetic screens linking metabolic and plasma proteomic profiles with causal effects are becoming an attractive approach in the cardiovascular precision medicine arena 35,36 and may provide both novel targets and/or an improved prognostic tool for stroke, ischaemic heart disease, and T2DM. 37…”

Section: Vascular Permeability and Inflammationmentioning

confidence: 99%

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis

Alexander

Osto

Schmidt‐Trucksäss

et al. 2020

Cardiovascular Research

225

183

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Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

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Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study

Cited by 21 publications

References 63 publications

Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes

Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes

Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis

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