This research seeks to investigate the function and fundamental mechanisms of Itchy E3 ubiquitin ligase (ITCH), a HECT (homologous to E6AP carboxyl terminus)-type E3 ubiquitin ligase, in endothelial ferroptosis, particularly in the context of atherosclerosis, which has been underexplored. The levels of ITCH protein in the aortas of mice with atherosclerosis were analyzed. Constructs for ITCH RNA interference were generated and introduced into human aortic endothelial cells (HAECs). The findings indicated that ITCH protein expression was elevated in atherosclerotic mice and HAECs exposed to oxidized low-density lipoprotein (ox-LDL). ITCH downregulation significantly mitigated ox-LDL-induced endothelial injury and dysfunction. Reducing ITCH expression inhibited ox-LDL-induced endothelial ferroptosis. This study also revealed that ITCH mediates ox-LDL-induced ubiquitin-dependent degradation of ferritin light chain (FTL) in HAECs. The protective impact of ITCH knockdown against ox-LDL-induced ferroptosis and endothelial injury was reversed by FTL siRNA. Additionally, in vivo experiments showed that inhibiting ITCH reduced atherosclerosis progression and reversed ferroptosis in the aorta, with an associated increase in FTL protein expression in the aortas of mice. This study demonstrates that ITCH interacts with and regulates the stability of the FTL protein via the ubiquitin-proteasome system, contributing to ox-LDL-induced ferroptosis and endothelial cell dysfunction. Targeting components of the ITCH-FTL pathway holds potential as a therapeutic strategy against atherosclerosis.

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms252413524DOI Listing

Publication Analysis

Top Keywords

endothelial ferroptosis
12
itch
10
itchy ubiquitin
8
ferritin light
8
light chain
8
ubiquitin ligase
8
itch protein
8
aortas mice
8
protein expression
8
ox-ldl-induced endothelial
8

Similar Publications

This research seeks to investigate the function and fundamental mechanisms of Itchy E3 ubiquitin ligase (ITCH), a HECT (homologous to E6AP carboxyl terminus)-type E3 ubiquitin ligase, in endothelial ferroptosis, particularly in the context of atherosclerosis, which has been underexplored. The levels of ITCH protein in the aortas of mice with atherosclerosis were analyzed. Constructs for ITCH RNA interference were generated and introduced into human aortic endothelial cells (HAECs).

View Article and Find Full Text PDF

Functional cell death pathways are essential for normal ocular vascular development and tissue homeostasis. As our understanding of necrosis-based cell death pathways has expanded, the inclusion of regulated forms, including necroptosis, ferroptosis, and oxytosis, has occurred. Although the existence of these pathways is well described, our understanding of their role during vascular development and pathological neovascularization is very limited.

View Article and Find Full Text PDF

Gastrodin protects against sepsis-associated encephalopathy by suppressing ferroptosis.

Shock

December 2024

Department of Pathology and Pathophysiology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, Yunnan, China.

Background: Sepsis-associated encephalopathy (SAE) represents a severe complication of sepsis, substantially elevating both mortality and healthcare costs for patients. Gastrodin (GAS), a principal bioactive constituent of Gastrodia elata Blume, is neuroprotective in various neurological disorders, including ischemic stroke, epilepsy, Alzheimer's disease, and neuropathic pain. In this study, we sought to investigate whether GAS could serve as a protective agent against SAE.

View Article and Find Full Text PDF

Atherosclerosis (AS) is a growing global health epidemic and is the leading cause of cardiovascular health problems, including ischemic stroke, coronary artery disease, and peripheral vascular disease. Despite extensive research on the underlying mechanisms of AS, iron remains an under-investigated mediator in the atherosclerotic process. Iron's involvement in AS is primarily linked to the iron-induced programmed cell death process known as ferroptosis.

View Article and Find Full Text PDF

This study is aimed at investigating the effects of atorvastatin (ATV) on endothelial cell injury in atherosclerosis (AS) through inhibiting acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to establish an in vitro model of AS. The cell viability, lactate dehydrogenase (LDH) release, apoptosis, and expression levels of apoptotic proteins were assessed.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!