Disturbed Tryptophan Metabolism in Cardiovascular Disease

Abstract

Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune-mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, pro-inflammatory cytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Among various other molecular and cellular effects, IFN- γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome.

Antioxidants, inflammation and cardiovascular disease

“…However, due the poor performance of antioxidant strategies in limiting atherosclerosis and cardiovascular events, it remains to be answered if oxidative modification is causal for the initiation or is an injurious response to atherogenesis [96] . Disease underlying interactions are too complex and the understanding is too fragmentary that clear, reliable therapeutic recommendations can be given [101] . The strong interconnection of metabolic and inflammatory pathways suggests that metabolically induced inflammatory processes should be considered as early, or even primary events [171] .…”

“…In this context, e.g., neopterin is a useful indicator of the immune activation status and oxidative stress [6] and Kyn/ Trp ratio accounts for aspects of immunoregulation via IDO and represents an important metabolic checkpoint. Normalization of tryptophan metabolism represents an important goal to improve the outcome of patients suffering from CVD, whereby treatments with IDO inhibitors such as 1-methyl tryptophan could be considered [101] . However, IDO is well known for its immunosuppressive properties, and its inhibition by medications may also lead to adverse effects.…”

“…Of note, development of depressive symptoms have been associated with increased CAD risk and poor prognosis [100] . Estimation of Trp breakdown rate could contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD [101] .…”

Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk

“…Kynurenine is a metabolite of tryptophan degradation, and previous studies (23,24) suggested that the Kyn/Trp ratio could be a potent indirect indicator of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of tryptophan catabolism. This pathway is induced by proinflammatory cytokines, especially interleukin-2, TNF-␣, and interferon-␥ (24).…”

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

“…Catabolites in the Kyn pathway of Trp catabolism are important for regulating the immune system and inflammation 10, 11. Emerging evidence also indicates that these catabolites play significant roles in cardiovascular pathophysiology 12, 13, 14…”