Immune activation and degradation of tryptophan in coronary heart disease.

BACKGROUND: Inflammation and immune activation appear to be important in the pathogenesis of coronary heart disease (CHD). Cytokine interferon-gamma, which is released during cell-mediated immune responses, induces indoleamine (2,3)-dioxygenase (IDO), an enzyme degrading tryptophan to kynurenine. Therefore, immune stimulation is commonly associated with an increased kynurenine to tryptophan ratio (kyn trp-1) indicative for activated indoleamine (2,3)-dioxygenase and a measurable decline of tryptophan. METHODS: Blood concentrations of kynurenine and free tryptophan and the kynurenine to tryptophan ratio were examined in 35 patients with coronary heart disease verified by coronary angiography and compared with healthy controls. Patients were observed before percutaneous transluminal coronary angioplasty (21 patients: one with artery disease, nine with 2- or 3-artery disease, and five with restenosis). RESULTS AND CONCLUSIONS: Decreased tryptophan concentrations were found in a significant proportion of coronary heart disease patients and coincided with increased kyn trp-1 and also with increased neopterin concentrations, indicating an activated cellular immune response. We conclude that in coronary heart disease immune activation is associated with an increased rate of tryptophan degradation and thereby lowered tryptophan levels. Results may provide a basis for a better understanding of the pathogenesis of mood disturbances and depression in coronary heart disease patients.

The influence of kynurenine, neopterin, and norepinephrine on tubular epithelial cells and alveolar fibroblasts.

We have examined the effect of kynurenine, neopterin and norepinephrine on epithelial cells and fibroblasts: the total DNA synthesis (by adding 3H-thymidine), the mitotic index, the amount of pathological mitosis and apoptosis. We have observed that kynurenine, neopterin and norepinephrine induce pathological mitosis and apoptosis of epithelial cells of kidney. The total DNA synthesis increases by the incubation of the epithelial cells with neopterin and norepinephrine. We have found an increase of pathological mitosis after addition of kynurenine, neopterin and norepinephrine to fibroblast cell culture. The total DNA synthesis is promoted by neopterin and norepinephrine, while kynurenine does not alter it. These data allow us to suggest that kynurenine, neopterin and norepinephrine promote epithelial cell damage leading to cell death through apoptosis, and can therefore be added to the factors, which promote the pathological mitosis of fibroblasts.

Changes in membrane fluidity induced by tryptophan and its metabolites.

Incorporation of fatty acids into phospholipids as well as cholesterol and phospholipid concentration has been investigated using samples of rat liver homogenate, Krebs-Ringer-phosphate buffer (pH = 7.4), containing 0.3% albumin, fatty acid mixture and glycerol. The addition of kynurenine, kynurenic, xanthurenic, picolinic, and 5-hydroxyindoleacetic acids to incubation medium for phospholipid biosynthesis in vitro induced the elevation of cholesterol/phospholipid ratio, cholesterol concentration in samples, an increase of saturated and a decrease of polyunsaturated fatty acids, especially arachidonic acid incorporation into phospholipids. It allowed us to suggest that these metabolites of tryptophan can decrease the membrane fluidity, depress cell cycle, cell transformation and may stimulate cholesterol precipitation. The addition of tryptophan, 3-hydroxykynurenine, 3-hydroxyanthranilic, quinolinic, nicotinic acids, serotonin together with iproniasid, acetylserotonin, and melatonin to incubation medium for phospholipid biosynthesis in vitro induced an inverse relationship. Tryptophan and above mentioned metabolites decreased cholesterol/phospholipid ratio, cholesterol concentration in samples and incorporation of saturated fatty acids into phospholipids. The incorporation of polyunsaturated fatty acids, especially arachidonic acid increased. It allowed us to suggest that tryptophan and these metabolites, may increase membrane fluidity, stimulate cell cycle, cell transformation and can protect against cholesterol precipitation.

Kynurenine and neopterin in chronic glomerulonephritis.

The results of our clinical observations of 102 patients with chronic glomerulonephritis with normal renal function have shown that hyperkynureninemia in 22.5% of patients develops in cases of pyridoxal-5-phosphate deficiency (hyperkynureninemia after peroral L-tryptophan load), but in 14.8% of patients through the stimulation of the cellular immune system (hyperkynureninemia at fasting state, increase of serum neopterin concentration). In all 20 patients with chronic renal failure hyperkynureninemia develops due to decreased renal function (increased serum kynurenine, neopterin and creatinine concentrations). Therefore, L-tryptophan peroral loading test with the determination of serum concentration of kynurenine before and at 3rd hour after the load, as well as the detection of serum concentration of neopterin and creatinine are helpful for the differentiation of following pathologies in patients with chronic glomerulonephritis: pyridoxal-5-phosphate deficiency, cellular immune stimulation and chronic renal failure.

Serum kynurenine and neopterin concentrations in patients with cardiomyopathy.

Serum kynurenine and neopterin concentrations were determined in patients with hypertrophic (n = 22) and dilated (n = 23) cardiomyopathy. Significantly increased kynurenine and neopterin levels have been observed in cases of dilated cardiomyopathy. In these patients we found a positive correlation between serum kynurenine and neopterin levels (RS = 0.52, P less than 0.001). There existed several associations between the laboratory parameters neopterin and kynurenine and clinical findings, such as left ventricle (LV) systolic volume and LV circumferential fiber shortening velocity in patients with dilated cardiomyopathy (all P less than 0.05). In vitro, interferon-gamma induces the formation of neopterin in human monocytes/macrophages. Also the degradation of tryptophan via the kynurenine pathway is induced by interferon-gamma. Our data show that increased kynurenine as well as neopterin accumulation in serum are associated with severity of dilated cardiomyopathy. Thus, the data point to a role of immune activation in the pathogenesis of the disease.

Increased blood kynurenine level as a factor inhibiting the therapeutic effect of antihypertensive agents in combined long-term treatment of essential hypertension.

Results of a three-year antihypertensive combined treatment of 24 male patients with essential hypertension aged 35-55 years are presented. In all patients the blood serum kynurenine level after tryptophan load was determined before treatment and after the 1st, 2nd and 3rd years of therapy. It was found that in a part of patients the long-term administration of antihypertensive drugs led to an increased accumulation of kynurenine as a manifestation of pyridoxal-5-phosphate deficiency. The development and preservation of an increased blood kynurenine level interferes with the positive effects of antihypertensive therapy as regards both blood pressure and left ventricular myocardial mass reduction.

[Peculiarities of nicotinic acid formation in coronary heart disease with special reference to heart arrhythmias]. / Besonderheiten der Nikotinsäurebildung bei koronarer Herzkrankheit unter Berücksichtigung von Herzrhythmusstörungen.

The present work is divided into two parts: clinical observations and experimental investigations. The endogenic formation of nicotinic acid was decreased in all patients with ischaemic heart disease, and we have found an increased accumulation of kynurenine in blood serum after tryptophan loading in many cases - a clear indication of pyridoxal-5-phosphate (P-5-P) deficiency in the organism. The results of experimental investigations showed that L-kynurenine sulphate initiates cardiac dysrhythmias as well as dystrophic changes in cardiomyocytes. Both the clinical observations and experimental investigations point out a previously unknown pathogenetic mechanism for the ischaemic heart disease, and for bradyarrhythmia as well as myocardial cell failure, caused by P-5-P deficiency in the organism.