Smooth muscle cell-specific CD47 deletion suppresses atherosclerosis.

IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Naveed Pervaiz, Rashid Mehmood, Ravi Varma Aithabathula, Ishita Kathuria, WonMo Ahn, Britney-Thuy Le, Ki-Suk Kim, Udai P Singh, Gabor Csanyi, Bhupesh Singla
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引用次数: 0

Abstract

Background: Recent smooth muscle cell (SMC)-lineage tracing and single-cell RNA sequencing (scRNA-seq) experiments revealed a significant role of SMC-derived cells in atherosclerosis development. Further, thrombospondin-1 (TSP1), a matricellular protein, and activation of its receptor cluster of differentiation (CD) 47 have been linked with atherosclerosis. However, the role of vascular SMC TSP1-CD47 signaling in regulating VSMC phenotype and atherogenesis remains unknown.

Methods: We investigated the role of SMC CD47 activation by TSP1 in regulating VSMC phenotype and atherosclerosis development using various in vitro cell-based assays, molecular biological techniques, immunohistological approaches, reanalysis of publicly available scRNA-seq data, and cell-specific knockout mice.

Results: We observed elevated TSP1 expression in human atherosclerotic vascular tissues and VSMCs. TSP1-treated VSMCs exhibited decreased expression of contractile SMC markers (ACTA2, CNN1, and TAGLN) and increased proliferation. Additional experiments and reanalysis of the scRNA-seq dataset showed CD47 as the major TSP1 receptor in VSMCs, with its expression increased in SMC-derived modulated cells of murine atherosclerotic arteries. Knockdown of CD47 gene in human VSMCs upregulated expression of contractile SMC markers and abrogated TSP1's effects on these genes. SMC-specific Cd47 deletion in mice suppressed atherosclerotic lesion formation, reduced macrophage accumulation, and decreased necrotic area. However, no significant differences were observed in weight gain, liver and adipose tissue mass, plasma total cholesterol, and fasting blood glucose between control and SMC-restricted Cd47-deficient mice. Further experiments demonstrated increased efferocytosis of apoptotic CD47-silenced VSMCs by macrophages.

Conclusions: These findings suggest that CD47 plays a crucial role in regulating VSMC phenotype, and SMC-specific-Cd47 deletion suppresses atherosclerosis.

New and noteworthy: VSMC phenotypic switching contributes to atherosclerosis development. The present study reports the novel observations that Cd47 levels are upregulated in phenotypically modulated SMCs within atherosclerotic arteries and targeted deletion of Cd47 specifically in SMCs attenuates atherosclerosis. Mechanistic in vitro investigations further showed that TSP1-CD47 signaling regulates VSMC phenotype. Therefore, targeting SMC CD47 represents a promising therapeutic target to suppress atherogenesis.

背景:最近的平滑肌细胞(SMC)系谱追踪和单细胞 RNA 测序(scRNA-seq)实验发现,SMC 衍生细胞在动脉粥样硬化的发展中起着重要作用。此外,凝血酶原-1(TSP1)是一种母细胞蛋白,其受体分化簇(CD)47的激活与动脉粥样硬化有关。然而,血管SMC TSP1-CD47信号在调节VSMC表型和动脉粥样硬化发生中的作用仍然未知:方法:我们使用各种体外细胞检测方法、分子生物学技术、免疫组织学方法、重新分析公开的 scRNA-seq 数据以及细胞特异性基因敲除小鼠,研究了 TSP1 激活 SMC CD47 在调节 VSMC 表型和动脉粥样硬化发生中的作用:结果:我们观察到 TSP1 在人类动脉粥样硬化血管组织和 VSMC 中的表达升高。经 TSP1 处理的 VSMC 表现出收缩性 SMC 标志物(ACTA2、CNN1 和 TAGLN)表达减少和增殖增加。其他实验和对 scRNA-seq 数据集的重新分析表明,CD47 是 VSMC 中主要的 TSP1 受体,它在小鼠动脉粥样硬化的 SMC 衍生调节细胞中的表达增加。在人类 VSMC 中敲除 CD47 基因会上调收缩性 SMC 标记的表达,并减弱 TSP1 对这些基因的影响。小鼠SMC特异性Cd47缺失抑制了动脉粥样硬化病变的形成,减少了巨噬细胞的聚集,并缩小了坏死面积。然而,在体重增加、肝脏和脂肪组织质量、血浆总胆固醇和空腹血糖方面,对照组小鼠与限制 SMC 的 Cd47 缺失型小鼠之间没有观察到明显差异。进一步的实验表明,巨噬细胞对凋亡的 CD47 沉默 VSMC 的吞噬作用增强:这些研究结果表明,CD47 在调节 VSMC 表型中起着至关重要的作用,SMC 特异性-CD47 缺失可抑制动脉粥样硬化:VSMC表型转换有助于动脉粥样硬化的发展。本研究报告了一项新的观察结果,即在动脉粥样硬化表型调节的SMC中,Cd47水平上调,而在SMC中特异性靶向删除Cd47可减轻动脉粥样硬化。体外机制研究进一步表明,TSP1-CD47 信号调节 VSMC 表型。因此,靶向 SMC CD47 是抑制动脉粥样硬化发生的一个很有前景的治疗靶点。
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来源期刊
Life sciences
Life sciences 医学-药学
CiteScore
12.20
自引率
1.60%
发文量
841
审稿时长
6 months
期刊介绍: Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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