Role of myeloid-derived chemokine CCL5/RANTES at an early stage of atherosclerosis

Jongstra‐Bilen, Jenny; Tai, Kelly; Althagafi, Marwan G.; Siu, Allan; Scipione, Corey A.; Karim, Saraf; Polenz, Chanele K.; Ikeda, Jiro; Hyduk, Sharon J.; Cybulsky, Myron I.

doi:10.1016/j.yjmcc.2021.03.010

Cited by 22 publications

(18 citation statements)

References 43 publications

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“…The persistent accumulation of the macrophages within the arterial intima from the onset of the disease is one of the hallmarks of atherosclerosis. The recruitment of monocytes results in the enhanced infiltration of macrophages at an early-stage atherosclerosis, which can be mediated by myeloid cell-derived CCL5 ( Jongstra-Bilen et al, 2021 ). CCL19 modulates the inflammatory milieu in atherosclerotic lesions ( Akhavanpoor et al, 2014 ), and its upregulation exerts an underlying pathogenic role in plaque destabilization ( Damås et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

Yang

Cai

et al. 2022

Front. Pharmacol.

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Objective: Experimental and clinical evidence suggests that atherosclerosis is a chronic inflammatory disease. Our study was conducted for uncovering the roles of immune-associated genes during atherosclerotic plaque progression.Methods: Gene expression profiling of GSE28829, GSE43292, GSE41571, and GSE120521 datasets was retrieved from the GEO database. Three machine learning algorithms, least absolute shrinkage, and selection operator (LASSO), random forest, and support vector machine–recursive feature elimination (SVM-RFE) were utilized for screening characteristic genes among atherosclerotic plaque progression- and immune-associated genes. ROC curves were generated for estimating the diagnostic efficacy. Immune cell infiltrations were estimated via ssGSEA, and immune checkpoints were quantified. CMap analysis was implemented to screen potential small-molecule compounds. Atherosclerotic plaque specimens were classified using a consensus clustering approach.Results: Seven characteristic genes (TNFSF13B, CCL5, CCL19, ITGAL, CD14, GZMB, and BTK) were identified, which enabled the prediction of progression of atherosclerotic plaques. Higher immune cell infiltrations and immune checkpoint expressions were found in advanced-stage than in early-stage atherosclerotic plaques and were positively linked to characteristic genes. Patients could clinically benefit from the characteristic gene-based nomogram. Several small molecular compounds were predicted based on the characteristic genes. Two subtypes, namely, C1 immune subtype and C2 non-immune subtype, were classified across atherosclerotic plaques. The characteristic genes presented higher expression in C1 than in C2 subtypes.Conclusion: Our findings provide several promising atherosclerotic plaque progression- and immune-associated genes as well as immune subtypes, which might enable to assist the design of more accurately tailored cardiovascular immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

Yang

Cai

et al. 2022

Front. Pharmacol.

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“…Wire-injury induced neointima formation in the carotid artery of Apoe −/− mice showed that the systemic inhibition of CCL5 or P-selectin deficiency hindered neointima formation as well as monocyte infiltration ( 50 ). Furthermore, it could be demonstrated that CCL 5 mRNA and protein levels were upregulated in the aortic intima of Ldlr −/− mice fed a WD for 3 weeks and a function-blocking antibody to CCR5 significantly reduced monocyte recruitment into the lesions ( 18 ). Further investigations using a bone marrow transplantation (BMT) experiment demonstrated that hematopoietic CCL5 regulates monocyte recruitment and accumulation of macrophages in the lesions after 3 weeks of cholesterol-rich diet feeding of Ldlr −/− mice.…”

Section: Chemokinesmentioning

confidence: 99%

“…Further investigations using a bone marrow transplantation (BMT) experiment demonstrated that hematopoietic CCL5 regulates monocyte recruitment and accumulation of macrophages in the lesions after 3 weeks of cholesterol-rich diet feeding of Ldlr −/− mice. However, after 6 weeks of cholesterol-rich diet, CCL5 only plays a minor role in the recruitment of monocytes into the lesions suggesting that CCL5 only plays a role in early stages of lesion formation and subsequent vascular remodeling ( 18 ).…”

Section: Chemokinesmentioning

confidence: 99%

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Evans

Yerly

Vorst

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.

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“…CCL5 (C-C motif ligand 5, also known as RANTES) and CXCL10 (C-X-C motif chemokine ligand 10) are two well-known cytokines that promote monocyte recruitment and macrophage maturation to atherosclerotic plaques (66)(67)(68)(69). Increased serum levels of CCL5 and CXCL10 are associated with human atherosclerotic plaque progression and stability, and the inhibition of either cytokine reduced atherosclerosis in animal models (70,71).…”

Section: Discussionmentioning

confidence: 99%

Sox13 is a novel flow-sensitive transcription factor that prevents inflammation by repressing chemokine expression in endothelial cells

Demos

Johnson

Andueza

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerosis is a chronic inflammatory disease and occurs preferentially in arterial regions exposed to disturbed blood flow (d-flow) while the stable flow (s-flow) regions are spared. D-flow induces endothelial inflammation and atherosclerosis by regulating endothelial gene expression partly through the flow-sensitive transcription factors (FSTFs). Most FSTFs, including the well-known Kruppel-like factors KLF2 and KLF4, have been identified from in vitro studies using cultured endothelial cells (ECs). Since many flow-sensitive genes and pathways are lost or dysregulated in ECs during culture, we hypothesized that many important FSTFs in ECs in vivo have not been identified. We tested the hypothesis by analyzing our recent gene array and single-cell RNA sequencing (scRNAseq) and chromatin accessibility sequencing (scATACseq) datasets generated using the mouse partial carotid ligation model. From the analyses, we identified 30 FSTFs, including the expected KLF2/4 and novel FSTFs. They were further validated in mouse arteries in vivo and cultured human aortic ECs (HAECs). These results revealed 8 FSTFs, SOX4, SOX13, SIX2, ZBTB46, CEBPβ, NFIL3, KLF2, and KLF4, that are conserved in mice and humans in vivo and in vitro. We selected SOX13 for further studies because of its robust flow-sensitive regulation, preferential expression in ECs, and unknown flow-dependent function. We found that siRNA-mediated knockdown of SOX13 increased endothelial inflammatory responses even under the unidirectional laminar shear stress (ULS, mimicking s-flow) condition. To understand the underlying mechanisms, we conducted an RNAseq study in HAECs treated with SOX13 siRNA under shear conditions (ULS vs. oscillatory shear mimicking d-flow). We found 94 downregulated and 40 upregulated genes that changed in a shear- and SOX13-dependent manner. Several cytokines, including CXCL10 and CCL5, were the most strongly upregulated genes in HAECs treated with SOX13 siRNA. The robust induction of CXCL10 and CCL5 was further validated by qPCR and ELISA in HAECs. Moreover, the treatment of HAECs with Met-CCL5, a specific CCL5 receptor antagonist, prevented the endothelial inflammation responses induced by siSOX13. In addition, SOX13 overexpression prevented the endothelial inflammation responses. In summary, SOX13 is a novel conserved FSTF, which represses the expression of pro-inflammatory chemokines in ECs under s-flow. Reduction of endothelial SOX13 triggers chemokine expression and inflammatory responses, a major proatherogenic pathway.

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Role of myeloid-derived chemokine CCL5/RANTES at an early stage of atherosclerosis

Cited by 22 publications

References 43 publications

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Sox13 is a novel flow-sensitive transcription factor that prevents inflammation by repressing chemokine expression in endothelial cells

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