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12 pages, 5814 KiB

Open AccessArticle

Atherogenesis in Apoe^−/− and Ldlr^−/− Mice with a Genetically Resistant Background

by Hideyuki Torikai, Mei-Hua Chen, Li Jin, Jiang He, John F. Angle and Weibin Shi

Cells 2023, 12(9), 1255; https://doi.org/10.3390/cells12091255 - 26 Apr 2023

Cited by 1 | Viewed by 1761

Abstract

Apoe-deficient (Apoe^−/−) and Ldlr-deficient (Ldlr^−/−) mice are two common animal models of hypercholesterolemia and atherosclerosis. The two models differ in lipid and glucose metabolism and other mechanisms involved in atherogenesis. Here we examined atherosclerotic lesion [...] Read more.

Apoe-deficient (Apoe^−/−) and Ldlr-deficient (Ldlr^−/−) mice are two common animal models of hypercholesterolemia and atherosclerosis. The two models differ in lipid and glucose metabolism and other mechanisms involved in atherogenesis. Here we examined atherosclerotic lesion formation in the two models with an atherosclerosis-resistant C3H/HeJ (C3H) background. 3-month-old C3H-Ldlr^−/− and C3H-Apoe^−/− mice developed minimal atherosclerotic lesions in the aortic root when fed a chow diet. After 12 weeks on a Western diet, C3H-Ldlr^−/− mice developed 3-fold larger lesions than C3H-Apoe^−/− mice in the aortic root (127,386 ± 13,439 vs. 41,542 ± 5075 μm²/section; p = 0.00028), but neither knockout formed any lesion in the carotid artery. After being ligated near its bifurcation, the common carotid artery developed intimal lesions in both knockouts 4 weeks after ligation, significantly larger in C3H-Ldlr^−/− than C3H-Apoe^−/− mice (68,721 ± 2706 vs. 47,472 ± 8146 μm²/section; p = 0.028). Compared to C3H-Apoe^−/− mice, C3H-Ldlr^−/− mice showed a 50% reduction in plasma MCP-1 levels, similar levels of malondialdehyde, an oxidative stress biomarker, on both chow and Western diets, but higher small dense LDL levels on the Western diet. These results suggest a more significant role for small dense LDL than inflammation and oxidative stress in the different susceptibility of the mouse models to atherosclerosis. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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11 pages, 2179 KiB

Open AccessArticle

11,12-EET Regulates PPAR-γ Expression to Modulate TGF-β-Mediated Macrophage Polarization

by Xiaoming Li, Sebastian Kempf, Stefan Günther, Jiong Hu and Ingrid Fleming

Cells 2023, 12(5), 700; https://doi.org/10.3390/cells12050700 - 23 Feb 2023

Cited by 4 | Viewed by 2816

Abstract

Macrophages are highly plastic immune cells that can be reprogrammed to pro-inflammatory or pro-resolving phenotypes by different stimuli and cell microenvironments. This study set out to assess gene expression changes associated with the transforming growth factor (TGF)-β-induced polarization of classically activated macrophages into [...] Read more.

Macrophages are highly plastic immune cells that can be reprogrammed to pro-inflammatory or pro-resolving phenotypes by different stimuli and cell microenvironments. This study set out to assess gene expression changes associated with the transforming growth factor (TGF)-β-induced polarization of classically activated macrophages into a pro-resolving phenotype. Genes upregulated by TGF-β included Pparg; which encodes the transcription factor peroxisome proliferator-activated receptor (PPAR)-γ, and several PPAR-γ target genes. TGF-β also increased PPAR-γ protein expression via activation of the Alk5 receptor to increase PPAR-γ activity. Preventing PPAR-γ activation markedly impaired macrophage phagocytosis. TGF-β repolarized macrophages from animals lacking the soluble epoxide hydrolase (sEH); however, it responded differently and expressed lower levels of PPAR-γ-regulated genes. The sEH substrate 11,12-epoxyeicosatrienoic acid (EET), which was previously reported to activate PPAR-γ, was elevated in cells from sEH^−/− mice. However, 11,12-EET prevented the TGF-β-induced increase in PPAR-γ levels and activity, at least partly by promoting proteasomal degradation of the transcription factor. This mechanism is likely to underlie the impact of 11,12-EET on macrophage activation and the resolution of inflammation. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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19 pages, 3114 KiB

Open AccessArticle

Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function

by Marc Dorenkamp, Madina Nasiry, Dilvin Semo, Sybille Koch, Ivonne Löffler, Gunter Wolf, Holger Reinecke and Rinesh Godfrey

Cells 2023, 12(3), 513; https://doi.org/10.3390/cells12030513 - 3 Feb 2023

Cited by 9 | Viewed by 2485

Abstract

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the [...] Read more.

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter—induced by MG or AGE-BSA—was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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19 pages, 4618 KiB

Open AccessArticle

Phenotypic and Genetic Evidence for a More Prominent Role of Blood Glucose than Cholesterol in Atherosclerosis of Hyperlipidemic Mice

by Ashley M. Abramson, Lisa J. Shi, Rebecca N. Lee, Mei-Hua Chen and Weibin Shi

Cells 2022, 11(17), 2669; https://doi.org/10.3390/cells11172669 - 28 Aug 2022

Viewed by 1702

Abstract

Hyperlipidemia and type 2 diabetes (T2D) are major risk factors for atherosclerosis. Apoe-deficient (Apoe^−/−) mice on certain genetic backgrounds develop hyperlipidemia, atherosclerosis, and T2D when fed a Western diet. Here, we sought to dissect phenotypic and genetic relationships of [...] Read more.

Hyperlipidemia and type 2 diabetes (T2D) are major risk factors for atherosclerosis. Apoe-deficient (Apoe^−/−) mice on certain genetic backgrounds develop hyperlipidemia, atherosclerosis, and T2D when fed a Western diet. Here, we sought to dissect phenotypic and genetic relationships of blood lipids and glucose with atherosclerotic plaque formation when the vasculature is exposed to high levels of cholesterol and glucose. Male F2 mice were generated from LP/J and BALB/cJ Apoe^−/− mice and fed a Western diet for 12 weeks. Three significant QTL Ath51, Ath52 and Ath53 on chromosomes (Chr) 3 and 15 were mapped for atherosclerotic lesions. Ath52 on proximal Chr15 overlapped with QTL for plasma glucose, non-HDL cholesterol, and triglyceride. Atherosclerotic lesion sizes showed significant correlations with fasting, non-fasting glucose, non-fasting triglyceride, and body weight but no correlation with HDL, non-HDL cholesterol, and fasting triglyceride levels. Ath52 for atherosclerosis was down-graded from significant to suggestive level after adjustment for fasting, non-fasting glucose, and non-fasting triglyceride but minimally affected by HDL, non-HDL cholesterol, and fasting triglyceride. Adjustment for body weight suppressed Ath52 but elevated Ath53 on distal Chr15. These results demonstrate phenotypic and genetic connections of blood glucose and triglyceride with atherosclerosis, and suggest a more prominent role for blood glucose than cholesterol in atherosclerotic plaque formation of hyperlipidemic mice. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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16 pages, 2179 KiB

Open AccessArticle

Neutrophil Counts, Neutrophil-to-Lymphocyte Ratio, and Systemic Inflammatory Response Index (SIRI) Predict Mortality after Off-Pump Coronary Artery Bypass Surgery

by Tomasz Urbanowicz, Michał Michalak, Anna Olasińska-Wiśniewska, Michał Rodzki, Anna Witkowska, Aleksandra Gąsecka, Piotr Buczkowski, Bartłomiej Perek and Marek Jemielity

Cells 2022, 11(7), 1124; https://doi.org/10.3390/cells11071124 - 26 Mar 2022

Cited by 52 | Viewed by 4710

Abstract

Background: Several perioperative inflammatory markers are postulated to be significant factors for long-term survival after off-pump coronary artery bypass surgery (OPCAB). Hematological parameters, whether single or combined as indices, provide higher predictive values. Methods: The study group comprised 538 consecutive patients (125 (23%) [...] Read more.

Background: Several perioperative inflammatory markers are postulated to be significant factors for long-term survival after off-pump coronary artery bypass surgery (OPCAB). Hematological parameters, whether single or combined as indices, provide higher predictive values. Methods: The study group comprised 538 consecutive patients (125 (23%) females and 413 (77%) males) with a mean age of 65 ± 9 years, who underwent OPCAB with a mean follow-up time of 4.7 ± 1.7 years. This single-center retrospective analysis included perioperative inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR), systemic inflammatory response index (SIRI), aggregate index of systemic inflammation (AISI), and systemic inflammatory index (SII). Results: Multivariable analysis identified levels of neutrophils above 4.3 × 10⁹/L (HR 13.44, 95% CI 1.05–3.68, p = 0.037), values of SIRI above 5.4 (HR 0.29, 95% CI 0.09–0.92, p = 0.036) and values of NLR above 3.5 (HR 2.21, 95% CI 1.48–3.32, p < 0.001) as being significant predictors of long-term mortality. The multifactorial models revealed the possibility of strong prediction by combining preoperative factors (COPD, stroke, PAD, and preoperative PLR) and postoperative neutrophil counts (p = 0.0136) or NLR (p = 0.0136) or SIRI (p = 0.0136). Conclusions: Among the postoperative inflammatory indices, the levels of neutrophils, NLR, and SIRI are the most prominent markers for long-term survival after off-pump coronary artery bypass surgery, when combined with preoperative characteristics. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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13 pages, 2629 KiB

Open AccessFeature PaperArticle

Reticulocalbin 2 as a Potential Biomarker and Therapeutic Target for Atherosclerosis

by Jing Li, Angela M. Taylor, Ani Manichaikul, John F. Angle and Weibin Shi

Cells 2022, 11(7), 1107; https://doi.org/10.3390/cells11071107 - 25 Mar 2022

Cited by 3 | Viewed by 2636

Abstract

Vascular inflammation initiated by oxidized lipoproteins drives initiation, progression, and even rupture of atherosclerotic plaques. Yet, to date, no biomarker is directly linked to oxidized lipid-induced vascular inflammation. Reticulocalbin 2 (RCN2) is a key regulator of basal and oxidized lipid-induced cytokine production in [...] Read more.

Vascular inflammation initiated by oxidized lipoproteins drives initiation, progression, and even rupture of atherosclerotic plaques. Yet, to date, no biomarker is directly linked to oxidized lipid-induced vascular inflammation. Reticulocalbin 2 (RCN2) is a key regulator of basal and oxidized lipid-induced cytokine production in arterial wall cells. We evaluated the potential of circulating RCN2 to identify subjects with or at risk of developing atherosclerosis. Immunohistochemical analysis revealed abundant RCN2 expression in the endothelium and adventitia of normal arteries and in atherosclerotic lesions of both humans and mice. Atherosclerosis-susceptible C57BL/6 (B6) mice had higher plasma Rcn2 levels than resistant C3H mice. High-fat diet feeding raised plasma Rcn2 levels of both strains. In humans, patients with coronary artery disease (CAD) or peripheral artery disease (PAD) showed elevated serum RCN2 levels compared to healthy controls. In a cohort of 92 CAD patients, serum RCN2 exhibited a significant inverse correlation with HDL cholesterol and K+ levels and a trend toward association with white blood cell account, Na+, statin treatment, and diastolic blood pressure. HDL treatment suppressed Rcn2 expression in endothelial cells. This study suggests that circulating RCN2 is a potential non-invasive biomarker for identifying individuals with atherosclerosis and HDL protects against atherosclerosis by downregulation of RCN2 expression in endothelial cells. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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8 pages, 252 KiB

Open AccessArticle

Osteopontin as Candidate Biomarker of Coronary Disease despite Low Cardiovascular Risk: Insights from CAPIRE Study

by Federico Carbone, Jennifer Meessen, Marco Magnoni, Daniele Andreini, Aldo Pietro Maggioni, Roberto Latini and Fabrizio Montecucco

Cells 2022, 11(4), 669; https://doi.org/10.3390/cells11040669 - 15 Feb 2022

Cited by 7 | Viewed by 2082

Abstract

Stratification according high cardiovascular (CV) risk categories, still represents a clinical challenge. In this analysis of the CAPIRE study (NCT02157662), we investigate whether inflammation could fit between CV risk factors (RFs) and the presence of coronary artery disease (CAD). In total, 544 patients [...] Read more.

Stratification according high cardiovascular (CV) risk categories, still represents a clinical challenge. In this analysis of the CAPIRE study (NCT02157662), we investigate whether inflammation could fit between CV risk factors (RFs) and the presence of coronary artery disease (CAD). In total, 544 patients were included and categorized according with the presence of CAD and CV risk factor burden (low/multiple). The primary endpoint was to verify any independent association of neutrophil-related biomarkers with CAD across CV risk categories. The highest values of osteopontin (OPN) were detected in the low RF group and associated with CAD (23.2 vs. 19.4 ng/mL; p = 0.001), although no correlation with plaque extent and/or composition were observed. Conversely, myeloperoxidase (MPO) and resistin did not differ by CAD presence. Again, OPN was identified as independent variable associated with CAD but only in the low RF group (adjOR 8.42 [95% CI 8.42–46.83]; p-value = 0.015). As an ancillary finding, a correlation linked OPN with the neutrophil degranulation biomarker MPO (r = 0.085; p = 0.048) and resistin (r = 0.177; p = 3.4 × 10⁻⁵). In the present study, OPN further strengthens its role as biomarker of CAD, potentially bridging subclinical CV risk with development of atherosclerosis. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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21 pages, 1128 KiB

Open AccessReview

Innate Immune Memory in Monocytes and Macrophages: The Potential Therapeutic Strategies for Atherosclerosis

by Zhigang Guo, Lixue Wang, Hongjian Liu and Yuhuai Xie

Cells 2022, 11(24), 4072; https://doi.org/10.3390/cells11244072 - 15 Dec 2022

Cited by 13 | Viewed by 3361

Abstract

Atherosclerosis is a complex metabolic disease characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel. As the most abundant innate immune cells, monocyte-derived macrophages play a pivotal role in the inflammatory response, cholesterol metabolism, and [...] Read more.

Atherosclerosis is a complex metabolic disease characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel. As the most abundant innate immune cells, monocyte-derived macrophages play a pivotal role in the inflammatory response, cholesterol metabolism, and foam cell formation. In recent decades, it has been demonstrated that monocytes and macrophages can establish innate immune memory (also termed trained immunity) via endogenous and exogenous atherogenic stimuli and exhibit a long-lasting proinflammatory phenotype. The important cellular metabolism processes, including glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and cholesterol synthesis, are reprogrammed. Trained monocytes/macrophages with innate immune memory can be persistently hyperactivated and can undergo extensive epigenetic rewiring, which contributes to the pathophysiological development of atherosclerosis via increased proinflammatory cytokine production and lipid accumulation. Here, we provide an overview of the regulation of cellular metabolic processes and epigenetic modifications of innate immune memory in monocytes/macrophages as well as the potential endogenous and exogenous stimulations involved in the progression of atherosclerosis that have been reported recently. These elucidations might be beneficial for further understanding innate immune memory and the development of therapeutic strategies for inflammatory diseases and atherosclerosis. Full article

(This article belongs to the Special Issue The Role of Inflammation in Atherosclerosis and Coronary Artery Disease)

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