AMPA-Type Glutamate Receptors Associated With Vascular Smooth Muscle Cell Subpopulations in Atherosclerosis and Vascular Injury.
AMPA-Type Glutamate Receptors Associated With Vascular Smooth Muscle Cell Subpopulations in Atherosclerosis and Vascular Injury.
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DOI：
10.3389/fcvm.2021.655869
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发表时间：
2021
影响因子：
3.6
通讯作者：
Olofsson PS
中科院分区：
文献类型：
--
作者：
Gallina AL;Rykaczewska U;Wirka RC;Caravaca AS;Shavva VS;Youness M;Karadimou G;Lengquist M;Razuvaev A;Paulsson-Berne G;Quertermous T;Gisterå A;Malin SG;Tarnawski L;Matic L;Olofsson PS
目的：血管平滑肌细胞（VSMCs）是正常动脉和动脉粥样硬化斑块的关键成分。它们有能力通过表型调节来适应当地环境的变化。对VSMC表型变化的调控机制的进一步了解可能为心血管疾病（CVD）的治疗提供新的治疗靶点。在实验模型中，氨基酸谷氨酸与CVD风险和VSMC代谢相关，谷氨酸受体调节VSMC生物学并促进肺血管重塑。然而，谷氨酸信号在人类动脉粥样硬化中的作用尚未被探索。方法和结果：通过单细胞RNA测序和微阵列分析，我们在人类动脉粥样硬化病变的VSMCs中鉴定了谷氨酸受体和谷氨酸代谢相关酶。经免疫染色证实，受体亚基谷氨酸受体、离子亲性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型亚基1 （GRIA1）和2 （GRIA2）的表达仅限于间充质细胞，主要是VSMCs。在大鼠动脉损伤和修复模型中，在与VSMC增殖、迁移和表型调节相关的时间点上，GRIA1和GRIA2 mRNA水平的变化最为明显。在体外，人颈动脉SMCs表达GRIA1，选择性ampa型受体阻断抑制典型收缩标志物的表达，促进与VSMC表型调节相关的途径。在我们的人颈动脉内膜切除术生物库中，ampa型受体亚基的低表达与炎症细胞含量较高和中风等不良临床事件的高频率相关。结论：ampa型谷氨酸受体在VSMCs中表达，并与表型调节有关。与无症状患者相比，有不良临床事件的患者其动脉粥样硬化病变中GRIA1和GRIA2 mRNA水平显著降低。这些结果为进一步绘制人类动脉粥样硬化发病机制中的神经递质信号提供了依据。
Objectives and Aims: Vascular smooth muscle cells (VSMCs) are key constituents of both normal arteries and atherosclerotic plaques. They have an ability to adapt to changes in the local environment by undergoing phenotypic modulation. An improved understanding of the mechanisms that regulate VSMC phenotypic changes may provide insights that suggest new therapeutic targets in treatment of cardiovascular disease (CVD). The amino-acid glutamate has been associated with CVD risk and VSMCs metabolism in experimental models, and glutamate receptors regulate VSMC biology and promote pulmonary vascular remodeling. However, glutamate-signaling in human atherosclerosis has not been explored. Methods and Results: We identified glutamate receptors and glutamate metabolism-related enzymes in VSMCs from human atherosclerotic lesions, as determined by single cell RNA sequencing and microarray analysis. Expression of the receptor subunits glutamate receptor, ionotropic, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type subunit 1 (GRIA1) and 2 (GRIA2) was restricted to cells of mesenchymal origin, primarily VSMCs, as confirmed by immunostaining. In a rat model of arterial injury and repair, changes of GRIA1 and GRIA2 mRNA level were most pronounced at time points associated with VSMC proliferation, migration, and phenotypic modulation. In vitro, human carotid artery SMCs expressed GRIA1, and selective AMPA-type receptor blocking inhibited expression of typical contractile markers and promoted pathways associated with VSMC phenotypic modulation. In our biobank of human carotid endarterectomies, low expression of AMPA-type receptor subunits was associated with higher content of inflammatory cells and a higher frequency of adverse clinical events such as stroke. Conclusion: AMPA-type glutamate receptors are expressed in VSMCs and are associated with phenotypic modulation. Patients suffering from adverse clinical events showed significantly lower mRNA level of GRIA1 and GRIA2 in their atherosclerotic lesions compared to asymptomatic patients. These results warrant further mapping of neurotransmitter signaling in the pathogenesis of human atherosclerosis.
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影响因子：
81.5
作者：
Libby, Peter;Buring, Julie E.;Lewis, Eldrin F.
通讯作者：
Lewis, Eldrin F.
影响因子：
3.5
作者：
Bonaz, B.;Sinniger, V.;Pellissier, S.
通讯作者：
Pellissier, S.
影响因子：
5.3
作者：
Inanaga, Keita;Ichiki, Toshihiro;Sunagawa, Kenji
通讯作者：
Sunagawa, Kenji
DOI：
10.1161/atvbaha.114.303892
发表时间：
2014-12-01
影响因子：
8.7
作者：
Johansson, Maria E.;Ulleryd, Marcus A.;Hansson, Goran K.
通讯作者：
Hansson, Goran K.
影响因子：
--
作者：
Caravaca, A S;Centa, M;Olofsson, P S
通讯作者：
Olofsson, P S