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

Abstract

Majority of translational research is focused on the use of rodent models to understand the pathophysiology of human disease. However, many experimental findings of rodent models fail to translate to human. In this regard, our previous studies show that LIM and cysteine‐rich domains 1 (LMCD1) plays a role in thrombin‐induced vascular smooth muscle cell (VSMC) proliferation and migration only in human but not rodents. Based on these findings, we asked the question whether LMCD1 exhibits any species‐specific role in the development of vascular lesions. 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 VSMC proliferation and migration during vascular wall remodeling in human versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells (HASMCs) but not mouse aortic smooth muscle cells (MASMCs). We found association of ‘rapid promoter evolution’ in this expression divergence of LMCD1 in human versus mice. In exploring the mechanism, we found that Par1‐Gαq/11‐PLCβ3‐NFATc1 signaling axis mediates thrombin‐induced LMCD1 expression in HASMCs. Furthermore, although LMCD1 mediates thrombin‐induced proliferation and migration of both HASMCs and MASMCs via influencing CDC6 and IL‐33 expression, respectively, in humans it acts as an activator and in mice it acts as a repressor of their promoters. Interestingly, its repressor activity was revoked by its myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to non‐stenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to non‐injured arteries. Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in human 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.Support or Funding InformationThis work was supported by a grant HL069908 from NIH to Dr. Gadiparthi N. Rao