OBJECTIVE In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions. Approach and Results: A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCβ3 (phospholipase Cβ3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2-mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries. CONCLUSIONS Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.

中文翻译：

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LMCD1 的肉豆蔻酰化导致其物种特异性去抑制 E2F1 和 NFATc1，从而调节血管病变发展过程中的 CDC6 和 IL-33 表达。

目的 鉴于我们之前对人类与啮齿动物中 LMCD1（LIM 和富含半胱氨酸结构域 1）表达差异的观察，我们提出了 LMCD1 是否在血管病变的发展中发挥物种特异性作用的问题。方法和结果：结合遗传、分子、细胞和疾病模型来测试 LMCD1 在血管病变发病机制中的物种特异性作用。在这里，我们报告了人类与小鼠血管壁重塑过程中 LMCD1 表达在介导血管平滑肌细胞增殖和迁移中的物种特异性调节。凝血酶通过激活 Par1（蛋白酶激活受体 1）-Gαq/11（Gα 蛋白 q/11）-PLCβ3（磷脂酶 Cβ3）-NFATc1（核因子）诱导人主动脉平滑肌细胞而非小鼠主动脉平滑肌细胞中 LMCD1 表达激活的 T 细胞 1) 信号传导。此外，尽管LMCD1通过影响E2F1（E2F转录因子1）介导的CDC6（细胞分裂周期6）表达和NFATc1介导的IL（白细胞介素）介导凝血酶诱导的人主动脉平滑肌细胞和小鼠主动脉平滑肌细胞的增殖和迁移。 )-33 分别表达，在人类中，它充当这些转录因子的激活剂，而在小鼠中，它充当这些转录因子的阻抑剂。有趣的是，小鼠体内 N-肉豆蔻酰转移酶 2 介导的肉豆蔻酰化作用使 LMCD1 阻遏物活性无效。此外，我们发现与非狭窄动脉相比，人类狭窄动脉中 LMCD1 的表达增加。另一方面，与未受伤的动脉相比，小鼠受伤动脉的新内膜病变中 LMCD1 的表达降低。结论 总之，这些观察结果表明，LMCD1 在人和小鼠中分别作为 E2F1 和 NFATc1 的激活剂和抑制剂，在血管病变发展过程中诱导 CDC6 和 IL-33 表达。基于这些发现，LMCD 可能成为抗人类再狭窄和动脉粥样硬化药物开发的潜在靶点。