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  • Myristoylation of LMCD1 Leads to Its Species-Specific Derepression of E2F1 and NFATc1 in the Modulation of CDC6 and IL-33 Expression During Development of Vascular Lesions.

Myristoylation of LMCD1 Leads to Its Species-Specific Derepression of E2F1 and NFATc1 in the Modulation of CDC6 and IL-33 Expression During Development of Vascular Lesions.

Arteriosclerosis, thrombosis, and vascular biology (2020-03-13)
Suresh Govatati, Prahalathan Pichavaram, Jagadeesh Janjanam, Liang Guo, Renu Virmani, Gadiparthi N Rao
摘要

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. 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.

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Sigma-Aldrich
单克隆抗-肌动蛋白,α-平滑肌, clone 1A4, ascites fluid
Sigma-Aldrich
Thrombin 来源于人类血浆, lyophilized powder, Suitable for routine use in the thrombin time test
Sigma-Aldrich
L-(−)-二硫苏糖醇, ≥95% (titration)
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MISSION® esiRNA, targeting human NMT1
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Anti-LMCD1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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MISSION® esiRNA, targeting human NMT2
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MISSION® esiRNA, targeting human LMCD1
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MISSION® esiRNA, targeting human ARHGAP4