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

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.

The inhibitor of autophagy SBI‑0206965 aggravates atherosclerosis through decreasing myeloid‑derived suppressor cells

“…In this study, 6965, a novel inhibitor of ULK1, was found to enhance the formation of atherosclerotic lesions and reduced plaque stability; reflected in increased plaque size, reduced SMC content, and increased proportion of macrophage infiltration and apoptosis. Although a few studies have associated inhibition of autophagy with anti-atherosclerotic capacity (19,20), most studies harmonize with the present conclusions, where inhibition of autophagy results in aggravation of AS. The conflicting results may be due to the heterogeneous modes of action of the various molecules implemented to inhibit autophagy in previous studies.…”

“…However, previous research shows conflicting results concerning the impact of the inhibition of autophagy on AS with some studies indicating impaired autophagy promotes this process (14)(15)(16)(17)(18) and others suggesting otherwise. For example, Chen et al (19) found inhibition of autophagy in endothelial cells provided anti-atherosclerotic effects. Similarly, Dai et al (20) found 3-methyladenine (3-MA), a widely used inhibitor of autophagy, hindered the formation of atherosclerotic lesions and increased plaque stabilization.…”

Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway

“…A work showing that rhTM activates the Akt pathway in endothelial cells supports this finding. 55 Activation of the Akt signaling pathway may further potentiate the rhTM effect by increasing the GPR15 surface expression. 56 These observations indicate that rhTM protects podocytes from apoptosis in our TGFb1-TG mice by activating the GPR15/Akt axis leading to enhanced expression of antiapoptotic factors and decreased expression of proapoptotic factors.…”

Effects of probucol on atherosclerotic plaque and soluble thrombomodulin in patients with coronary heart disease

“…It is a determinant of thrombosis in the inner lining of blood vessels. Improving thrombomodulin level in blood was directly related to the alleviation of symptoms of patients with atherosclerosis, and played an important role in enhancing anticoagulation in patients and preventing thrombosis ( 18 , 19 ). Correlation analysis in this study showed that a positive correlation between the plasma thrombomodulin level and atherosclerotic plaque area (r=0.725, P=0.008).…”