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Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.

ABSTRACT: The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell-specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development.Using Chat-H-deficient bone marrow transplantation in low-density lipoprotein receptor-deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6c(high) and nonclassical Ly6c(low) monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This associated with defective adhesion of Chat-H-deficient Ly6c(high) and Ly6c(low) monocytes to vascular cell adhesion molecule-1 in vitro and impaired infiltration of fluorescent bead-loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes.Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis.

SUBMITTER: Herbin O

PROVIDER: S-EPMC5001917 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.

Herbin Olivier O Regelmann Adam G AG Ramkhelawon Bhama B Weinstein Erica G EG Moore Kathryn J KJ Alexandropoulos Konstantina K

Arteriosclerosis, thrombosis, and vascular biology 20160714 9

<h4>Objective</h4>The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell-specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development.<h4>Approach and results</h4>Using Chat-H-deficient bone marrow ...[more]

PMID: 27417580

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Project description:BackgroundAtherosclerotic plaque instability is a common cause of stroke and ischemic infarction, and identification of monocyte-associated genes has become a prominent feature in cardiovascular research as a contributing/predictive marker.MethodsWhole genome sequencing data were downloaded from GSE159677, GSE41571, GSE120521, and GSE118481. Single-cell sequencing data analysis was conducted to cluster molecular subtypes of atherosclerotic plaques and identify specific genes. Differentially expressed genes (DEGs) between normal subjects and patients with unstable atheromatous plaques were screened. Weighted gene coexpression network analysis (WGCNA) was performed to find key module genes. In addition, GO and KEGG enrichment analyses explored potential biological signaling pathways to generate protein interaction (PPI) networks. GSEA and GSVA demonstrated activations in plaque instability subtypes.Results239 monocyte-associated genes were identified based on bulk and single-cell RNA-sequencing, followed by the recognition of 1221 atherosclerotic plaque-associated DEGs from the pooled matrix. GO and KEGG analyses suggested that DEGs might be related to inflammation response and the PI3K-Akt signaling pathway. Eight no-grey modules were obtained through WGCNA analysis, and the turquoise module has the highest correlation with unstable plaque (R 2 = 0.40), which contained 1323 module genes. After fetching the intersecting genes, CXCL3, FPR1, GK, and LST1 were obtained that were significantly associated with plaque instability, which had an intense specific interaction. Monocyte-associated genes associated with atherosclerotic plaque instability have certain diagnostic significance and are generally overexpressed in this patient population. In addition, 11 overlapping coexpressed genes (CEG) might also activated multiple pathways regulating inflammatory responses, platelet activation, and hypoxia-inducible factors. GSVA showed that the corresponding pathways were significantly activated in high expression samples.ConclusionsOverexpression of CXCL3, GK, FPR1, and LST1 was advanced recognition and intervention factors for unstable plaques, which might become targets for atherosclerosis rupture prevention. We also analyzed the potential mechanisms of CEG from inflammatory and oxidative stress pathways.

Dataset Information

Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.

Publications

Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.

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