FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress

TL;DR

This study shows that FBXO38 reduces vascular damage by controlling Nox1 levels under abnormal blood flow conditions.

Contribution

FBXO38 is newly identified as a regulator of Nox1 stability in endothelial cells under low oscillatory shear stress.

Findings

FBXO38 overexpression reduces Nox1 accumulation and ROS production under low oscillatory shear stress.

Loss of FBXO38 leads to increased Nox1 levels and endothelial apoptosis in vitro and in vivo.

FBXO38 directly interacts with Nox1, suggesting a ubiquitin-dependent degradation mechanism.

Abstract

Oxidative stress and endothelial dysfunction are critical drivers of atherosclerosis, but the mechanisms regulating oxidative stress under disturbed flow conditions remain incompletely understood. The ubiquitin–proteasome system, particularly E3 ubiquitin ligases, may play a pivotal role in modulating these processes. FBXO38, an E3 ligase involved in proteasomal degradation, has been implicated in various physiological pathways, but its role in regulating oxidative stress in endothelial cells is unknown. We hypothesized that FBXO38 mitigates endothelial damage induced by low oscillatory shear stress (LOSS) by promoting the ubiquitin–proteasome–dependent degradation of Nox1, a major source of reactive oxygen species (ROS). Using an in vitro LOSS model in human umbilical vein endothelial cells (HUVECs) and an in vivo mouse partial carotid ligation model, we assessed the expression of FBXO38 and Nox1 through quantitative PCR, western blotting, immunofluorescence, and immunohistochemistry. LOSS significantly reduced FBXO38 protein expression (by ~60%, p < 0.0001 at 24 h), leading to increased Nox1 protein levels (approximately two-fold, p < 0.001) and apoptosis. FBXO38 overexpression markedly attenuated Nox1 accumulation (~50% reduction, p < 0.05), reduced ROS production, and improved cell viability under LOSS conditions, whereas FBXO38 knockdown exacerbated these effects. Moreover, FBXO38 directly interacted with Nox1, suggesting a ubiquitin-dependent degradation mechanism. Our results reveal that FBXO38 regulates endothelial oxidative stress by controlling Nox1 stability under disturbed shear stress conditions. Although FBXO38 emerges as a promising candidate for therapeutic targeting, further studies are necessary to validate its potential in preclinical and clinical settings.

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