Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice

doi:10.1038/s41598-017-03443-z

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Title:	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
Authors:	Chen, Po-Sheng Wang, Kuan-Chieh Chao, Ting-Hsing Chung, Hsing-Chun Tseng, Shi-Ya Luo, Chawn-Yau Shi, Guey-Yueh Wu, Hua-Lin Li, Yi-Heng
Contributors:	Natl Cheng Kung Univ Hosp & Coll Med, Dept Internal Med Natl Cheng Kung Univ Hosp & Coll Med, Dept Biochem & Mol Biol Natl Cheng Kung Univ Hosp & Coll Med, Dept Surg Natl Cheng Kung Univ Hosp & Coll Med, Inst Clin Med Chia Nan Univ Pharm & Sci, Dept Tourism Management, Coll Recreat & Hlth Management
Keywords:	Soluble Thrombomodulin Progenitor Cells Disease Domain Angiogenesis Dysfunction Migration Akt
Date:	2017-06-12
Issue Date:	2018-11-30 15:56:42 (UTC+8)
Publisher:	Nature Publishing Group
Abstract:	Stress-induced alteration in endothelial cells (ECs) integrity precedes the development of atherosclerosis. Previous studies showed that the soluble recombinant thrombomodulin (rTM) not only increases ECs proliferation but also exerts anti-apoptotic activity in ECs. However, the functional significance of soluble rTM on autophagy-related apoptosis in ECs is still undetermined. Implicating a cytoprotective role for rTM in persistent serum starvation (SS)-induced autophagy in cultured ECs, we found that treatment of rTM decreased the expression of SS-induced autophagy-related proteins, ATG5 and LC3, and the formation of autophagosomes through activation of AKT/mTOR pathway. In addition, treatment of rTM decreased SS-induced EC apoptosis, but this effect of rTM could not be recapitulated by co-treatment with a potent autophagy inducer, rapamycin and in ECs with ATG5 knockdown. In human atherosclerosis specimens, expression of autophagy markers, ATG13 and LC3, were more abundant in aortic intimal ECs with severe atherosclerosis than those without atherosclerosis. Moreover, compared to saline treatment group, administration of rTM reduced LC3 and ATG13 expression, intimal EC apoptosis, and atherosclerotic lesion severity in the aorta of apolipoprotein E deficient mice. In conclusion, treatment with rTM suppressed stress-induced autophagy overactivation in ECs, provided ECs protective effects, and decreased atherosclerosis in apolipoprotein E deficient mice.
Relation:	Scientific Reports, v.7, pp.3284
Appears in Collections:	[Dept. of Tourism Management] Periodical Articles

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