Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.
Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.
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DOI：
10.1038/s44161-022-00042-8
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
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作者：
Cheng, Paul;Wirka, Robert C;Kim, Juyong Brian;Kim, Hyun-Jung;Nguyen, Trieu;Kundu, Ramendra;Zhao, Quanyi;Sharma, Disha;Pedroza, Albert;Nagao, Manabu;Iyer, Dharini;Fischbein, Michael P;Quertermous, Thomas
动脉粥样硬化斑块主要由平滑肌细胞 (SMC) 组成，影响 SMC 表型的基因可以调节冠状动脉疾病 (CAD) 风险。全基因组关联研究已鉴定出 15q22.33 的等位基因变异可降低 CAD 风险，并与 SMC 中 SMAD3 的表达相关。然而，人们对该基因改变 CAD 风险的机制仍知之甚少。在这里，我们表明，在小鼠动脉粥样硬化模型中，SMC 特异性删除 Smad3 会导致更大的斑块负担、更多的向外重塑和增加的血管钙化。单细胞转录组分析显示，Smad3 的缺失改变了 SMC 细胞状态向两种命运的转变：控制血管重塑和炎症细胞招募的 SMC 表型，以及软骨肌细胞的命运。总之，这些研究结果表明，SMC 中的 Smad3 表达抑制特定 SMC 表型过渡细胞的出现，这些细胞介导不良斑块特征，包括向外重塑、单核细胞募集和血管钙化。
Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification.