Key result
TFEB overexpression reduced endothelial inflammation in diabetic mice by suppressing IKK activity and NF-κB signaling, an effect mediated by KLF2 in response to laminar flow.
Why the study?
To investigate whether TFEB regulates endothelial inflammation in diabetic db/db mice and elucidate the underlying molecular mechanisms.
Does TFEB overexpression reduce endothelial inflammation in diabetic db/db mice and human umbilical vein endothelial cells?
Does TFEB overexpression reduce endothelial inflammation in diabetic db/db mice and human umbilical vein endothelial cells?
TFEB exerts anti-inflammatory effects in the endothelium of diabetic mice by inhibiting the IKK-p65 pathway, highlighting its potential as a therapeutic target for vascular inflammation.
TFEB may reduce diabetic endothelial inflammation; hypothesis-generating in mice, human validation required before any clinical consideration.
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-κB (nuclear factor-kappa B) signaling. Indeed, luciferase assay shows TFEB suppresses NF-κB transcriptional activity. Mechanistically, TFEB suppresses IKK (IκB kinase) activity to protect IκB-α 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 (Krüppel-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 IκBα level to suppress NF-κB activity. KLF2 mediates TFEB upregulation in response to laminar flow.
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Song et al. (2019) studied Vascular inflammation in diabetes. TFEB overexpression vs. Control was evaluated on Endothelial inflammation and NF-κB signaling. TFEB overexpression reduced endothelial inflammation in diabetic mice by suppressing IKK activity and NF-κB signaling, an effect mediated by KLF2 in response to laminar flow.
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