Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial β1 Integrin

Hu, Shuhong; Liu, Yifei; You, Tao; Heath, Jonathon; Xu, Linru; Zheng, Xiaowei; Wang, Aili; Wang, Yinyan; Li, Fengchan; Yang, Fei; Cao, Yiren; Zhang, Huayu; Gils, Janine M. van; Zonneveld, Anton Jan van; Jo, Hanjoong; Wu, Qingyu; Zhang, Yonghong; Tang, Chaojun; Zhu, Li

doi:10.1161/atvbaha.117.310491

Cited by 63 publications

(76 citation statements)

References 43 publications

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“…Subsequent work has shown that it enhances autoimmune encephalitis through Tcell-dependent cytokine production and that it can also increase the infiltration of neutrophils into sites of tissue hypoxia 19,20 . A role for Sema7a in the cardiovascular system has been described recently in atherogenesis 21 . Hu et al showed that disturbed flow resulted in an induction of Sema7a on vascular endothelium and that this results in an increased expression of leukocyte adhesion molecules on the endothelial surface.…”

mentioning

confidence: 93%

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

Köhler¹,

Granja²,

Volz³

et al. 2020

Nat Commun

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Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet-neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet-neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury.

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mentioning

confidence: 93%

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

Köhler¹,

Granja²,

Volz³

et al. 2020

Nat Commun

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“…Synthetically considering the atheroprotection induced by Sema7A gene knockout in animal models 19 Considering potential limitations of this study, our results should be interpreted cautiously. The current study is a case-control study with a relatively small study population, and with the nature of the cross section for the association of Sema7A with AAS because measurements of Sema7A were only obtained after AAS onset.…”

Section: Ta B L E 1 Baseline Characteristics Of 105 Acute Atherothrommentioning

confidence: 89%

Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke

You

Zhu

Zheng

et al. 2019

J Cellular Molecular Medi

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Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age‐ and sex‐matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high‐density lipoprotein (HDL)‐cholesterol, low‐density lipoprotein (LDL)‐cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88‐14.25). Each 1‐standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84‐6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS.

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“…Sema3E also inhibits smooth muscle cell migration and proliferation, decreasing neointimal hyperplasia in animal model of atherosclerosis ( 23 ). Different from Sema3A and 3E, Sema7A favors atherosclerotic plaque development by increasing endothelial dysfunction in a β1 integrin-dependent manner ( 24 ). In fact, vessels under oscillatory disturbed shear stress show higher Sema7A levels, while Sema7A knockout (ko) mice have attenuated plaque formation ( 24 ).…”

Section: Atherosclerosis and Semaphorinsmentioning

confidence: 99%

CD100 Effects in Macrophages and Its Roles in Atherosclerosis

Luque

Galuppo

Capelli-Peixoto

et al. 2018

Front. Cardiovasc. Med.

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CD100 or Sema4D is a protein from the semaphorin family with important roles in the vascular, nervous and immune systems. It may be found as a membrane bound dimer or as a soluble molecule originated by proteolytic cleavage. Produced by the majority of hematopoietic cells including B and T lymphocytes, natural killer and myeloid cells, as well as endothelial cells, CD100 exerts its actions by binding to different receptors depending on the cell type and on the organism. Cell-to-cell adhesion, angiogenesis, phagocytosis, T cell priming, and antibody production are examples of the many functions of this molecule. Of note, high CD100 serum levels has been found in inflammatory as well as in infectious diseases, but the roles of the protein in the pathogenesis of these diseases has still to be clarified. Macrophages are highly heterogeneous cells present in almost all tissues, which may change their functions in response to microenvironmental conditions. They are key players in the innate and adaptive immune responses and have decisive roles in sterile conditions but also in several diseases such as atherosclerosis, autoimmunity, tumorigenesis, and antitumor responses, among others. Although it is known that macrophages express CD100 and its receptors, few studies have focused on the role of this semaphorin in this cell type or in macrophage-associated diseases. The aim of this review is to critically revise the available data about CD100 and atherosclerosis, with special emphasis on its roles in macrophages and monocytes. We will also describe the few available data on treatments with anti-CD100 antibodies in different diseases. We hope that this review stimulates future studies on the effects of such an important molecule in a cell type with decisive roles in inflammatory diseases such as atherosclerosis.

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Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial β1 Integrin

Abstract: Our findings indicate a significant role of Sema7A in atherosclerosis by mediating endothelial dysfunction in a β1 integrin-dependent manner.

Cited by 63 publications

References 43 publications

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke

CD100 Effects in Macrophages and Its Roles in Atherosclerosis

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