Fibrillin-1 mutation contributes to Marfan syndrome by inhibiting Cav1.2-mediated cell proliferation in vascular smooth muscle cells.

Wenfeng Lin, Jiaqi Xiong, Yefan Jiang, Hao Liu, Jinhui Bian, Juejin Wang, Yongfeng Shao, Buqing Ni
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Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutation in fibrillin-1 (FBN1). However, the molecular mechanism underlying MFS remains poorly understood. The study aimed to explore how the L-type calcium channel (CaV1.2) modulates disease progression of MFS and to identify a potential effective target for attenuating MFS. KEGG enrichment analysis showed that the calcium signaling pathway gene set was significantly enriched. We demonstrated that FBN1 deficiency exhibited inhibition on both the expression of Cav1.2 and proliferation of vascular smooth muscle cells (VSMCs). Then, we examined whether FBN1 mediates Cav1.2 via regulating TGF-β1. Higher levels of TGF-β1 were observed in the serum and aortic tissues from patients with MFS. TGF-β1 modulated Cav1.2 expression in a concentration-dependent manner. We evaluated the role of Cav1.2 in MFS by small interfering RNA and Cav1.2 agonist Bay K8644. The effect of Cav1.2 on cell proliferation was dependent on c-Fos activity. These results demonstrated FBN1 deficiency decreased the expression levels of Cav1.2 via regulation of TGF-β1, and downregulation of Cav1.2 inhibited cell proliferation of human aortic smooth muscle cells (HASMCs) in MFS patients. These findings suggest that Cav1.2 may be an appealing therapeutic target for MFS.

纤颤蛋白1突变通过抑制血管平滑肌细胞中cav1.2介导的细胞增殖而导致马凡氏综合征。
马凡氏综合征(MFS)是一种由原纤维蛋白-1(FBN1)突变引起的常染色体显性结缔组织疾病。然而,MFS的分子机制仍知之甚少。本研究旨在探索L型钙通道(CaV1.2)如何调节MFS的疾病进展,并确定一个潜在的有效靶点来减轻MFS。KEGG富集分析表明,钙信号通路基因集显著富集。我们证明FBN1缺乏对Cav1.2的表达和血管平滑肌细胞(VSMCs)的增殖都表现出抑制作用。然后,我们检测了FBN1是否通过调节TGF-β1介导Cav1.2。在MFS患者的血清和主动脉组织中观察到较高水平的TGF-β1。TGF-β1以浓度依赖的方式调节Cav1.2的表达。我们通过小干扰RNA和Cav1.2激动剂Bay K8644评估了Cav1.2在MFS中的作用。Cav1.2对细胞增殖的影响依赖于c-Fos活性。这些结果表明,FBN1缺乏通过调节TGF-β1降低了Cav1.2的表达水平,并且下调Cav1.2抑制了MFS患者中人主动脉平滑肌细胞(HASMCs)的细胞增殖。这些发现表明Cav1.2可能是MFS的一个有吸引力的治疗靶点。
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