| First Author | Song W | Year | 2019 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 39 |
| Issue | 4 | Pages | 719-730 |
| PubMed ID | 30816805 | Mgi Jnum | J:291376 |
| Mgi Id | MGI:6443893 | Doi | 10.1161/ATVBAHA.119.312316 |
| Citation | Song W, et al. (2019) Endothelial TFEB (Transcription Factor EB) Restrains IKK (IkappaB Kinase)-p65 Pathway to Attenuate Vascular Inflammation in Diabetic db/db Mice. Arterioscler Thromb Vasc Biol 39(4):719-730 |
| abstractText | Objective- TFEB (transcription factor EB) was recently reported to be induced by atheroprotective laminar flow and play an anti-atherosclerotic role by inhibiting inflammation in endothelial cells (ECs). This study aims to investigate whether TFEB regulates endothelial inflammation in diabetic db/db mice and the molecular mechanisms involved. Approach and Results- Endothelial denudation shows that TFEB is mainly expressed in ECs in mouse aortas. Western blotting shows TFEB total protein level decreases whereas the p-TFEB S142 (phosphorylated form of TFEB) increases in db/db mouse aortas, suggesting a decreased TFEB activity. Adenoviral TFEB overexpression reduces endothelial inflammation as evidenced by decreased expression of vascular inflammatory markers in db/db mouse aortas, and reduced expression of a wide range of adhesion molecules and chemokines in human umbilical vein ECs. Monocyte attachment assay shows TFEB suppresses monocyte adhesion to human umbilical vein ECs. RNA sequencing of TFEB-overexpressed human umbilical vein ECs suggested TFEB inhibits NF-kappaB (nuclear factor-kappa B) signaling. Indeed, luciferase assay shows TFEB suppresses NF-kappaB transcriptional activity. Mechanistically, TFEB suppresses IKK (IkappaB kinase) activity to protect IkappaB-alpha from degradation, leading to reduced p65 nuclear translocation. Inhibition of IKK by PS-1145 abolished TFEB silencing-induced inflammation in human umbilical vein ECs. Lastly, we identified KLF2 (Kruppel-like factor 2) upregulates TFEB expression and promoter activity. Laminar flow experiment showed that KLF2 is required for TFEB induction by laminar flow and TFEB is an anti-inflammatory effector downstream of laminar flow-KLF2 signaling in ECs. Conclusions- These findings suggest that TFEB exerts anti-inflammatory effects in diabetic mice and such function in ECs is achieved by inhibiting IKK activity and increasing IkappaBalpha level to suppress NF-kappaB activity. KLF2 mediates TFEB upregulation in response to laminar flow. |
