PM-induced inflammation and lipidome alteration associated with the development of atherosclerosis based on a targeted lipidomic analysis. Zhang Jingyi,Liang Shuang,Ning Ruihong,Jiang Jinjin,Zhang Jie,Shen Heqing,Chen Rui,Duan Junchao,Sun Zhiwei Environment international Epidemiological studies have confirmed that PM could contribute to the development of atherosclerosis accompanied with lipids dysregulation. However, the lipids biomarkers involved in this progress remain largely unknown. In this study, a targeted lipidomic approach was used to find out the possible lipid biomarkers involved in the development of atherosclerosis after PM exposure or during a recovery period. Also, we assessed the pro-atherosclerosis effects of PM and follow-up influence using pulse wave (PW) Doppler ultrasound, oil red O staining and H&E staining. The vascular stiffness was elevated after 2-month PM exposure and might persist after 1-month recovery. While the lesions mostly concentrated in the aortic arch was significantly increased in 2-month PM exposure group and remained an increasing trend after 1-month recovery. The expressions of pro-inflammatory cytokines detected by Mouse Inflammation Array were elevated after ApoE mice treated with PM for 2-month and restored following 1-month recovery. Yet, IL-10 was significantly decreased during 1-month recovery. Additionally, the targeted lipidomic analysis demonstrated that cholesterol ester (CE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM) were significantly increased while lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), diacylglycerol (DG), triacylglycerol (TG) were reduced after 2-month PM exposure, indicating that PM could disrupt glycerophospholipids, glycerolipids and sphingolipids metabolism. And a persistent impact of PM on glycerophospholipids and glycerolipids metabolism was found after 1-month recovery. Our study demonstrated that PM-induced inflammation response might promote atherosclerotic lesions probably through lipid dysregulation, and the influence probably persisted after 1-month recovery. 10.1016/j.envint.2019.105444

Prediction of the localization of high-risk coronary atherosclerotic plaques on the basis of low endothelial shear stress: an intravascular ultrasound and histopathology natural history study. Chatzizisis Yiannis S,Jonas Michael,Coskun Ahmet U,Beigel Roy,Stone Benjamin V,Maynard Charles,Gerrity Ross G,Daley William,Rogers Campbell,Edelman Elazer R,Feldman Charles L,Stone Peter H Circulation BACKGROUND:Low endothelial shear stress (ESS) promotes the development of atherosclerosis; however, its role in the progression of atherosclerotic plaques and evolution to inflamed high-risk plaques has not been studied. Our hypothesis was that the lowest values of ESS are responsible for the development of high-risk coronary atherosclerotic plaques associated with excessive expansive remodeling. METHODS AND RESULTS:Twenty-four swine, treated with streptozotocin to induce diabetes and fed a high-fat diet, were allocated into early (n=12) and late (n=12) atherosclerosis groups. Intima-media thickness was assessed by intravascular ultrasound in the coronary arteries at weeks 4 and 8 in the early group and weeks 23 and 30 in the late group. Plaques started to develop after week 8, leading to marked heterogeneity in plaque severity at week 30. ESS was calculated in plaque-free subsegments of interest (n=142) in the late group at week 23. Coronary arteries (n=31) of this group were harvested at week 30, and the subsegments of interest were identified and analyzed histopathologically. Low ESS was an independent predictor of the development of high-risk plaques, characterized by intense lipid accumulation, inflammation, thin fibrous cap, severe internal elastic lamina degradation, and excessive expansive remodeling. The severity of high-risk plaque characteristics at week 30 was significantly correlated with the magnitude of low ESS at week 23. CONCLUSIONS:The magnitude of low ESS determines the complexity and heterogeneity of atherosclerotic lesions and predicts the development of high-risk plaque. 10.1161/CIRCULATIONAHA.107.695254

Toll-like receptor 7 protects from atherosclerosis by constraining "inflammatory" macrophage activation. Salagianni Maria,Galani Ioanna E,Lundberg Anna M,Davos Constantinos H,Varela Aimilia,Gavriil Ariana,Lyytikäinen Leo-Pekka,Lehtimäki Terho,Sigala Fragiska,Folkersen Lasse,Gorgoulis Vassilis,Lenglet Sébastien,Montecucco Fabrizio,Mach François,Hedin Ulf,Hansson Göran K,Monaco Claudia,Andreakos Evangelos Circulation BACKGROUND:Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. METHODS AND RESULTS:We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe(-/-) mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C(hi) inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. CONCLUSIONS:These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy. 10.1161/CIRCULATIONAHA.111.067678

Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Denis Maxime,Marcinkiewicz Jadwiga,Zaid Ahmed,Gauthier Dany,Poirier Steve,Lazure Claude,Seidah Nabil G,Prat Annik Circulation BACKGROUND:The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low-density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in ≈7-fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis. METHODS AND RESULTS:We investigated the role of PCSK9 in atherosclerosis in C57BL/6 wild-type (WT), apolipoprotein E-deficient, and LDL receptor-deficient mouse models. Circulating cholesterol levels, fast protein liquid chromatography profiles, aortic cholesteryl esters (CE), and plaque sizes were determined. Intima-media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (knockout [KO]), normal (WT), or high (transgenic [Tg]) levels of PCSK9 were fed a 12-month Western diet. KO mice accumulated 4-fold less aortic CE than WT mice, whereas Tg mice exhibited high CE and severe aortic lesions. Next we generated apolipoprotein E-deficient mice, known to spontaneously develop lesions, that expressed null (KO/e), normal (WT/e), or high (Tg/e) levels of PCSK9. After a 6-month regular diet, KO/e mice showed a 39% reduction compared with WT/e mice in aortic CE accumulation, whereas Tg/e mice showed a 137% increase. Finally, LDL receptor-deficient mice expressing no (KO/L), normal (WT/L), or high (Tg/L) levels of PCSK9 were fed a Western diet for 3 months. KO/L and Tg/L mice exhibited levels of plasma cholesterol and CE accumulation similar to those of WT/L mice, suggesting that PCSK9 modulates atherosclerosis mainly via the LDL receptor. CONCLUSIONS:Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is proatherogenic, whereas its absence is protective. 10.1161/CIRCULATIONAHA.111.057406