Aims Atherosclerosis is a chronic inflammatory disease involving immunological and metabolic processes. Metabolism of tryptophan (Trp) via the kynurenine pathway has shown immunomodulatory properties and the ability to modulate atherosclerosis. We identified 3-hydroxyanthranilic acid (3-HAA) as a key metabolite of Trp modulating vascular inflammation and lipid metabolism. The molecular mechanisms driven by 3-HAA in atherosclerosis have not been completely elucidated. In this study, we investigated whether two major signalling pathways, activation of SREBPs and inflammasome, are associated with the 3-HAA-dependent regulation of lipoprotein synthesis and inflammation in the atherogenesis process. Moreover, we examined whether inhibition of endogenous 3-HAA degradation affects hyperlipidaemia and plaque formation. Methods and results In vitro, we showed that 3-HAA reduces SREBP-2 expression and nuclear translocation and apolipoprotein B secretion in HepG2 cell cultures, and inhibits inflammasome activation and IL-1β production by macrophages. Using Ldlr−/− mice, we showed that inhibition of 3-HAA 3,4-dioxygenase (HAAO), which increases the endogenous levels of 3-HAA, decreases plasma lipids and atherosclerosis. Notably, HAAO inhibition led to decreased hepatic SREBP-2 mRNA levels and lipid accumulation, and improved liver pathology scores. Conclusions We show that the activity of SREBP-2 and the inflammasome can be regulated by 3-HAA metabolism. Moreover, our study highlights that targeting HAAO is a promising strategy to prevent and treat hypercholesterolaemia and atherosclerosis.
Inflammasomes are intracellular protein platforms, which, upon activation, produce the highly proinflammatory cytokines interleukin (IL)-1β and IL-18. Heme, hemin and their degradation products possess significant immunomodulatory functions. Here, we studied whether hemin regulates inflammasome function in macrophages. Both hemin and its derivative, cobalt protoporphyrin (CoPP), significantly reduced IL-1β secretion by cultured human primary macrophages, the human monocytic leukemia cell line and also mouse bone marrow-derived and peritoneal macrophages. Intraperitoneal administration of CoPP to mice prior to urate crystal-induced peritonitis alleviated IL-1β secretion to the peritoneal cavity. In cultured macrophages, hemin and CoPP inhibited NLRP3 inflammasome assembly by reducing the amount of intracellular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). The reduction of ASC was associated with enhanced autophagosome formation and autophagic flux. Inhibition of autophagy prevented the CoPP-induced depletion of ASC, implying that the depletion was caused by increased autophagy. Our data indicate that hemin functions as an endogenous negative regulator of the NLRP3 inflammasome. The inhibition is mediated via enhanced autophagy that results in increased degradation of ASC. This regulatory mechanism may provide a novel approach for the treatment of inflammasome-related diseases.
The progression of equine odontoclastic tooth resorption and hypercementosis (EOTRH) has not been completely evaluated, and currently, the only effective treatment is extraction of severely affected teeth. We aim to describe how the disease relates to the history and clinical findings and to report on the outcome in individual horses. This case series comprises data collected from 20 horses (age 14–29 years old) with radiographic findings of EOTRH in their incisor and/or canine teeth. Most horses affected with EOTRH in this study were admitted for dental problems, but some for other complaints such as colic. Of the 288 teeth evaluated radiographically, 224 teeth were abnormal. Radiographic findings were most frequently located in the apical aspect and reserve crown of the teeth, and lesions were also commonly found in clinically normal teeth. Histopathology of extracted teeth showed inflammation in the periodontal ligament and revealed that resorption often extended to the dentine. Some owners were unwilling to allow extraction of their horses’ severely affected teeth, even though this treatment has been shown to increase the wellbeing of the horse. As EORTH is a life-long condition, the progression of the disease has to be continuously monitored and the treatments adjusted accordingly.
Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress.
Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified major metabolic step regulating inflammation. Whether the PDK/PDH axis plays role in vascular inflammation and atherosclerotic cardiovascular disease has never been studied. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe-/- mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans, and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe-/- mice. These results point toward a promising treatment to combat atherosclerosis.
ApoA-I, the main structural and functional protein of HDL particles, is cardioprotective, but also highly sensitive to proteolytic cleavage. Here, we investigated the effect of cardiac mast cell activation and ensuing chymase secretion on apoA-I degradation using isolated rat hearts in the Langendorff perfusion system. Cardiac mast cells were activated by injection of compound 48/80 into the coronary circulation or by low-flow myocardial ischemia, after which lipid-free apoA-I was injected and collected in the coronary effluent for cleavage analysis. Mast cell activation by 48/80 resulted in apoA-I cleavage at sites Tyr and Phe, but hypoxic activation at Tyr only. In vitro, the proteolytic end-product of apoA-I with either rat or human chymase was the Tyr-truncated fragment. This fragment, when compared with intact apoA-I, showed reduced ability to promote migration of cultured human coronary artery endothelial cells in a wound-healing assay. We propose that C-terminal truncation of apoA-I by chymase released from cardiac mast cells during ischemia impairs the ability of apoA-I to heal damaged endothelium in the ischemic myocardium.
The Eurasian lynx (Lynx lynx) despite the wide distribution has fragmented populations with possibly decreased genetic variability. Reports from Central Europe have raised cardiac health as possible risk factor for lynx populations. The knowledge on normal anatomic variations of lynx heart is crucial to assess emerging pathological or hereditary disorders. The aim of this study was to give a detailed description of the cardiac anatomy and circulation of the Eurasian lynx and to report the cardiac health of the lynx in Finland. The cardiac anatomy and pathology were studied post mortem from 63 legally hunted lynx. In general, the cardiac anatomy of Eurasian lynx corresponded with that described for other felids. In the ventricles, varying number of thin ventricular bands was a common feature and their histological appearance was characterized by a fibromuscular pattern. The size of the heart varied between males and females, but the relative size was similar to that described for most domesticated carnivores. No marked pathologic lesions were observed in the lynx hearts. Fibrosis was observed in 56% of the hearts, but it was focal and mild in degree and unlikely to affect cardiac function or to have clinical significance. In conclusion, the cardiac health of the Finnish Eurasian lynx population is good with no signs of heritable cardiac disorders. Furthermore, we were able to give a detailed anatomic description of the lynx heart, which can serve as a reference for further epidemiological investigations on cardiac diseases in lynx populations.
Supplementary key words bradykinin • cholesterol • foam cells • high density lipoprotein • histamine • lipoproteins • mast cells • serotoninVascular endothelium is a semipermeable barrier that regulates the solute composition of interstitial fl uids by an ultrafi ltration process of various blood components ( 1 ). Such a sieving effect also determines the passage through the endothelium of the various types of lipoproteins, which are the largest blood solutes. It was an early observation in hypercholesterolemic rabbits that the arterial infl ux of plasma HDL, LDL, and VLDL decreases linearly with the logarithm of the diameter of the lipoprotein particles ( 2 ). Studies in humans and other mammalian species also indicated that the fl ux of LDL from plasma into the arterial wall depends not only on its plasma concentration but also on its permeability at the plasma-arterial wall interface ( 3 ).Accumulation of excess cholesterol in cytoplasmic lipid droplets of macrophages in the arterial intima is a primary event in atherosclerosis. Accordingly, an efficient control of the cholesterol pool in the arterial foam cells is essential to prevent progression of the disease or even to induce its regression. In general, control of cellular cholesterol balance is partially achieved by the transfer of cellular cholesterol from peripheral body compartments to the liver and ultimately to the gut for its fecal excretion along a pathway that is known as the reverse cholesterol transport (RCT) ( 4 ). Effl ux of cellular
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