scholarly journals Endotoxinemia Accelerates Atherosclerosis via Electrostatic Charge-Mediated Monocyte Adhesion

Circulation ◽  
2020 ◽  
Author(s):  
Ariane Schumski ◽  
Almudena Ortega-Gómez ◽  
Kanin Wichapong ◽  
Carla Winter ◽  
Patricia Lemnitzer ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Acute Infection ◽  
Atherosclerotic Lesion ◽  
Myeloid Cell ◽  
Lesion Size ◽  
Histone H2a ◽  
Monocyte Adhesion ◽  
Arterial Lumen ◽  
Lps Treatment

Background: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide (LPS) derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here we utilize a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation. Methods: Acute infection was mimicked by injection of a single dose of LPS into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy. Results: LPS treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. LPS treatment led to the deposition of NETs along the arterial lumen and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we employed in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclical peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia. Conclusions: Our study shows, that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.

Abstract 17163: Nox4 Deletion Attenuates Age-Associated Vascular Inflammation and Atherosclerosis Burden in Hyperlipidemic Mice by Modulating Macrophage Phenotype

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Aleksandr E Vendrov ◽  
Andrey Lozhkin ◽  
Nageswara R Madamanchi ◽  
Marschall S Runge
Keyword(s):  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Inflammasome Activation ◽  
Macrophage Phenotype ◽  
Wild Type ◽  
Lesion Area ◽  
Atherosclerotic Lesions ◽  
M1 Phenotype ◽  
Inflammatory Macrophages ◽  
Lps Treatment

Introduction: Increased vascular reactive oxygen species (ROS) levels and chronic inflammation are hallmarks of vascular aging. We previously reported that expression of NOX4 NADPH oxidase increases with age in mouse and human arteries and correlates with inflammatory cytokine secretion and atherosclerotic lesion progression. Hypothesis: To determine whether NOX4 promotes atherosclerosis in aging, we assessed vascular inflammation and atherosclerosis burden in Nox4 -/- / Apoe -/- and Apoe -/- mice. Results: Aortic atherosclerotic lesion area was not different between 5-month old (young) Nox4 -/- / Apoe -/- and Apoe -/- mice fed a Western diet for 3 months. Lesion area increased significantly in 16-month old (aged) compared with young mice but was 51% lower in Nox 4 -/- / Apoe -/- versus Apoe -/- mice (n=12, P <0.0001). Immunofluorescence analysis of aorta transverse sections showed 30% lower ROS levels and significantly reduced expression of inflammatory cytokines - CCL2 and IL6 - in atherosclerotic lesions of aged Nox4 -/- / Apoe -/- versus Apoe -/- mice. Flow cytometry analysis of atherosclerotic aortas showed significantly higher number of CD11b + macrophages in the lesions of aged Apoe -/- versus Nox4 -/- /Apoe -/- mice. However, the number of M1 pro-inflammatory macrophages (CD38 + ) was not different, whereas percentage of M2 macrophages (Egr2 + ) was significantly higher in aged Nox4 -/- Apoe -/- versus Apoe -/- mice (46% vs. 33%, respectively). In addition, Nox4 deletion increased the ratio of M2/M1 macrophages in the atherosclerotic aortas from aged Apoe -/- mice (0.56 and 0.43 in Nox 4 -/- / Apoe -/- and Apoe -/- , respectively). Macrophages isolated from Nox4 -/- mice showed lower number of M1 cells after IFNγ+LPS treatment and higher number of M2 cells after IL4 treatment versus macrophages from the wild-type. Furthermore, wild-type macrophages showed significantly higher secreted IL1β levels after IFNγ+LPS treatment versus macrophages from Nox4 -/- mice. Conclusions: These data suggest that increased vascular NOX4 levels in aged Apoe -/- mice promote a proinflammatory environment, enhancing plaque macrophage accumulation and skewing polarization to M1 phenotype resulting in inflammasome activation and atherosclerotic lesion expansion.

scholarly journals Mechanistic Links between Non-Coding RNAs and Myeloid Cell Inflammation in Atherosclerosis

2019 ◽  
Vol 119 (08) ◽  
pp. 1205-1211
Author(s):  
Valentina Paloschi ◽  
Hanna Winter ◽  
Joana Viola ◽  
Oliver Soehnlein ◽  
Lars Maegdefessel
Keyword(s):  
Messenger Rna ◽  
Vascular Inflammation ◽  
Myeloid Cells ◽  
Atherosclerotic Lesion ◽  
Myeloid Cell ◽  
Ribonucleic Acids ◽  
Atherosclerosis Progression ◽  
Functional Studies ◽  
Non Coding Rnas ◽  
Atherosclerosis Development

AbstractInflammation plays a pivotal role in the chronicity of atherosclerotic lesion development and progression. Myeloid cells are involved in all stages of atherosclerosis development: they contribute in early phases to endothelial dysfunction and create a pro-inflammatory environment responsible for disease progression. Numerous studies over the last decade have repeatedly provided evidence for the crucial importance for different classes of non-coding ribonucleic acids (RNAs) in regulating gene expression, as well as messenger RNA and protein stability. Functional studies using tools to either over-express or inhibit these non-coding RNAs showcased strong effects on tempering vascular inflammation and atherosclerosis progression. With this current review article, we want to discuss prominent examples of non-coding RNAs, being either produced by myeloid cells or affecting their recruitment and activity in the context of vascular inflammation, atherosclerosis and consequential diseases (such as myocardial infarction and stroke). All of the discussed transcripts were thoroughly studied in mechanistic explorations, indicating that they have the capability to modulate inflammatory cascades in the vasculature during disease exacerbation.

scholarly journals Intermedin1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jin-Ling Ren ◽  
Yao Chen ◽  
Lin-Shuang Zhang ◽  
Ya-Rong Zhang ◽  
Shi-Meng Liu ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Lesion ◽  
Immunohistochemical Analysis ◽  
Inhibitory Effect ◽  
Lesion Size ◽  
Plaque Vulnerability ◽  
Macrophage Apoptosis ◽  
Advanced Lesion

AbstractAtherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE−/−) mice. Six-week IMD1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD1-53 administration prevented ERS activation in aortic lesions of ApoE−/− mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE−/− mice. IMD1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.

Abstract 417: AT2R Stimulation Prevents TNFa-Induced Vascular Inflammation In Vitro and Ex Vivo

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Amanda K Sampson ◽  
Jennifer C Irvine ◽  
Olivier Huet ◽  
Tyrone A Barnes ◽  
Robert E Widdop ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Early Event ◽  
Type I ◽  
Ros Production ◽  
Monocyte Adhesion ◽  
Intact Mouse ◽  
Anti Inflammatory

Vascular inflammation, involving the recruitment, adhesion and infiltration of monocytes to the sub-endothelial space, is a critical early event in the development of atherosclerosis. The renin angiotensin system plays an important role in inflammation via activation of the angiotensin type I receptor (AT1R), which induces pro-inflammatory effects. The angiotensin II type 2 receptor (AT2R) counter-regulates the effects of the AT1R, including AT1R-mediated pro-inflammatory cytokine expression. We investigated the anti-inflammatory effects of AT2R stimulation in vascular inflammation by examining leukocyte to endothelial adhesion. We quantified the effect of AT2R stimulation (Compound 21: C21, 100μM) on TNFα (10ng/mL)-induced monocyte adhesion to cultured human umbilical vascular endothelial cells in vitro . AT2R stimulation attenuated TNFα-induced monocyte adhesion (unstimulated: 8±4% of TNFα: 100%, C21+TNFα: 59±12% of TNFα-induced adhesion). Adhesion of monocytes to the endothelial monolayer following incubation with TNFα+C21+AT2R antagonism (PD 123319, 10μM) was not different to TNFα-induced monocyte adhesion (93±5% of TNFα); demonstrating that the anti-inflammatory effects of C21 are mediated by the AT2R. Furthermore, C21 treatment attenuated TNFα-induced upregulation of adhesion molecules ICAM-1 and E-selectin and abolished TNFα-induced ROS production (unstimulated: 2±2, TNFα: 55±16, TNFα+C21: -3±5 dihydroethidium fluorescence intensity units). We quantified TNFα-induced leukocyte adhesion in intact mouse thoracic aorta ex vivo in real time in the presence and absence of AT2R activation. Consistent with our in vitro findings, we observed that direct AT2R activation (C21, 10μM) abolished TNFα-induced leukocyte adhesion (TNFα: 30±4, vs TNFα+C21: 11±4 adhered leukocytes/field of view (FOV), P<0.01) an effect which was abolished by co-incubation with PD 123319 (10μM: 31±5 adhered leukocytes/FOV). This study provides the first functional evidence that direct AT2R stimulation prevents TNFα-induced leukocyte adhesion, ICAM-1 and E-selectin expression and ROS production revealing the anti-inflammatory and therapeutic potential of the AT2R in the treatment of inflammation-induced cardiovascular disease.

scholarly journals Reduced atherosclerosis lesion size, inflammatory response in miR-150 knockout mice via macrophage effects

2018 ◽  
Vol 59 (4) ◽  
pp. 658-669 ◽  
Author(s):  
Fu-Han Gong ◽  
Wen-Lin Cheng ◽  
Haiping Wang ◽  
Maomao Gao ◽  
Juan-Juan Qin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Knockout Mice ◽  
Noncoding Rna ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Endothelial Cell Proliferation ◽  
Double Knockout

Atherosclerosis is considered to be a chronic inflammatory disease that can lead to severe clinically important cardiovascular events. miR-150 is a small noncoding RNA that significantly enhances inflammatory responses by upregulating endothelial cell proliferation and migration, as well as intravascular environmental homeostasis. However, the exact role of miR-150 in atherosclerosis remains unknown. Here, we investigated the effect of miR-150 deficiency on atherosclerosis development. Using double-knockout (miR-150−/− and ApoE−/−) mice, we measured atherosclerotic lesion size and stability. Meanwhile, we conducted in vivo bone marrow transplantation to identify cellular-level components of the inflammatory response. Compared with mice deficient only in ApoE, the double-knockout mice had significantly smaller atherosclerotic lesions and displayed an attenuated inflammatory response. Moreover, miR-150 ablation promoted plaque stabilization via increases in smooth muscle cell and collagen content and decreased macrophage infiltration and lipid accumulation. The in vitro experiments indicated that an inflammatory response with miR-150 deficiency in atherosclerosis results directly from upregulated expression of the cytoskeletal protein, PDZ and LIM domain 1 (PDLIM1), in macrophages. More importantly, the decreases in phosphorylated p65 expression and inflammatory cytokine secretion induced by miR-150 ablation were reversed by PDLIM1 knockdown. These findings suggest that miR-150 is a promising target for the management of atherosclerosis.

scholarly journals CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Gang Wang ◽  
Jiao-Jiao Chen ◽  
Wen-Yi Deng ◽  
Kun Ren ◽  
Shan-Hui Yin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cholesterol Efflux ◽  
Lentiviral Vector ◽  
Macrophage Polarization ◽  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Novel Approach ◽  
Underlying Mechanisms

AbstractC1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

scholarly journals Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1394 ◽  
Author(s):  
Pablo Bilbao-Ramos ◽  
Dolores R. Serrano ◽  
Helga Karina Ruiz Saldaña ◽  
Juan J. Torrado ◽  
Francisco Bolás-Fernández ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Chronic Infection ◽  
Acute Infection ◽  
Parasite Burden ◽  
Immunological Response ◽  
Lesion Size ◽  
Experimental Models ◽  
Infection Model

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

Abstract 3373: MRP-8/14 is Critical for the Biological Response to Vascular Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kevin Croce ◽  
Huiyun Gao ◽  
Yunmei Wang ◽  
Masashi Sakuma ◽  
Toshifumi Mooroka ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Cellular Proliferation ◽  
Cell Function ◽  
Transcriptional Profiling ◽  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Biological Response ◽  
Myeloid Cell ◽  
Neutrophil Accumulation ◽  
Increased Risk

Background : MRP-8 (S100A8) and MRP-14 (S100A9) are members of the S100-family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of toll-like receptor-4 and RAGE. Using a transcriptional profiling approach in patients with acute coronary syndromes, we made the novel discovery that MRP-14 is associated with atherothrombosis, and demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Despite functioning as a pro-inflammatory mediator, the role of MRP-8/14 in vascular inflammation and disease are unknown. Methods and Results : We evaluated vascular inflammation in wild-type (WT) and MRP-14-deficient (MRP-14 −/− ) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14 −/− mice had a 33% reduction in leukocyte accumulation ( P =.0004) and a 72% reduction in cellular proliferation ( P =0.001) in the arterial wall followed by a 45% reduction in neointima formation ( P =0.004) compared to WT mice. In a cytokine-induced local Schwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14 −/− mice had a 59% reduction in lesion severity ( P <0.0001), an 82% smaller hemorrhagic area ( P =0.015), and a 45% decline in neutrophil accumulation ( P =0.013). Finally, in response to high-fat feeding, mice doubly deficient in ApoE and MRP-8/14 complexes had attenuation in atherosclerotic lesion area by 34% ( P =0.023) and a 60% decrease in macrophage accumulation in plaques ( P =0.021) compared to mice deficient in ApoE alone. Conclusions: This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury. Targeting MRP-8/14 may provide a novel therapeutic approach to modulate diverse forms of vascular injury, including restenosis, vasculitis, and atherosclerosis.

Abstract 22: Absence of Circadian Gene Bmal in Macrophage Enhances Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Xiao Yu Tian ◽  
Yuhong Huang ◽  
Wing Tak Wong ◽  
Ajay Chawla ◽  
Yu Huang
Keyword(s):  
Circadian Rhythm ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Myeloid Cell ◽  
Control Flow ◽  
Peripheral Cell ◽  
Atherosclerotic Plaque Formation ◽  
En Face ◽  
Inflammatory Macrophages

Backgrounds: Peripheral cell-intrinsic clock is present in all types of cells and is important for synchronization of physiological function in response to changes of environment. Bmal (encoded by Arntl gene) is a transcription factor that forms complex with Clock and induces rhythmic transcription. Peripheral clock has been demonstrated in monocyte to regulate inflammatory responses. In this regards, we hypothesize that disruption of circadian rhythm in myeloid cells enhances atherosclerosis in Apoe -/- mice. Methods and Results: Apoe -/- mice housed under weekly switch between regular (ZT12-ZT0: dark) and inverted (ZT12-ZT0: light) ligh/dark cycle developed more atherosclerotic lesion than Apoe-/- mice housed under regular L/D cycle. Myeloid cell-specific Bmal knockout mice ( Arntl LoxP/LoxP Lyz2 Cre ) as Bmal MKO and Bmal wild type ( Arntl LoxP/ LoxP ) as Bmal MWT were crossbred with Apoe-/- to generate Apoe-Bmal MKO and Apoe-Bmal MWT mice. Mice with disruption of myeloid circadian rhythm (Apoe-Bmal MKO ) on Western diet showed enhanced atherosclerotic plaque formation by en face oil red o staining, compared with their WT control. Flow cytometry showed more infiltrating macrophages within the plaque of Apoe-Bmal MKO mice, accompanied with upregulation of proinflammatory genes Tnf, Il1b, Nos2, S100a8; chemokines and adhesion molecules Vcam1, Icam1, Sele, Ccl2, Ccl8; and downregulation of anti-inflammatory genes. Aortic root staining showed more macrophages by CD68 staining, more CD11c + pro-inflammatory macrophages, and more Ly6c + infiltrating monocyte-derived macrophages in Apoe-Bmal MKO mice. In vitro culture of bone marrow derived macrophage from Apoe-Bmal MKO and Apoe-Bmal MWT mice demonstrated that deletion of myeloid Bmal impaired rhythmic transcription of Ccl2 and Ccl8, causing higher expressions. Meanwhile, lipid profile and endothelial function were unaltered in Apoe-Bmal MKO compared with Apoe-Bmal MWT mice. Conclusions: Our data showed disruption of myeloid circadian rhythm increased inflammation and enhanced atherosclerosis

scholarly journals Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3517
Author(s):  
Julian Friebel ◽  
Eileen Moritz ◽  
Marco Witkowski ◽  
Kai Jakobs ◽  
Elisabeth Strässler ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Inflammatory Cells ◽  
Endothelial Activation ◽  
Lesion Size ◽  
Pleiotropic Effects ◽  
Knock Out ◽  
Cytokines And Chemokines ◽  
Protease Activated Receptor 1 ◽  
Vascular Adhesion

Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. Methods and Results: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E–knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. Conclusions: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.

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