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Articles by M. R Lee
Total Records ( 2 ) for M. R Lee
  H. J Jeon , J. H Choi , I. H Jung , J. G Park , M. R Lee , M. N Lee , B Kim , J. Y Yoo , S. J Jeong , D. Y Kim , J. E Park , H. Y Park , K Kwack , B. K Choi , B. S Kwon and G. T. Oh
 

Background— The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation.

Methods and Results— We generated CD137-deficient apolipoprotein E–knockout mice (ApoE–/– CD137–/–) and LDL-receptor–knockout mice (Ldlr–/–CD137–/–) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-, monocyte chemoattractant protein-1, and tumor necrosis factor-. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels.

Conclusions— CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.

  M. N Lee , S. N Lee , S. H Kim , B Kim , B. K Jung , J. H Seo , J. H Park , J. H Choi , S. H Yim , M. R Lee , J. G Park , J. Y Yoo , J. H Kim , S. T Lee , H. M Kim , S Ryeom , K. W Kim and G. T. Oh
  Background

Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A225) acetylates HIF-1, triggering its degradation, and thus may play a role in decreased expression of VEGFA.

Methods

We generated ApcMin/+/mARD1A225 transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A225 were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A225 acetylation of Lys532 in HIF-1, we injected B16F10-mARD1A225 cell lines stably expressing mutant HIF-1/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.

Results

ApcMin/+/mARD1A225 transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than ApcMin/+ mice (n = 21) (number of intestinal polyps per mouse: ApcMin/+ mice vs ApcMin/+/mARD1A225 transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A225-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A225 decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and ApcMin/+ intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1 in B16F10-mARD1A225 cells prevented HIF-1 degradation and inhibited the antimetastatic effect of mARD1A225 (P < .001).

Conclusion

mARD1A225 may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.

 
 
 
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