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NEDD4L-mediated RASGRP2 suppresses high-glucose and oxLDL-induced vascular endothelial cell dysfunctions by

Guozhu Chen1, Yisong Pei1, Qiaoling Ye1

  • 1The Second Affiliated Hospital of Chongqing Medical University Cardiology Department, Chongqing, China.

Biochimica Et Biophysica Acta. Molecular Cell Research
|September 11, 2024
PubMed
Abstract

Insights

Ras guanyl-releasing protein 2 (RASGRP2) protects against diabetes mellitus-related atherosclerosis by improving endothelial cell function. Targeting the NEDD4L/RASGRP2 pathway or using RASGRP2-modified exosomes offers a potential therapeutic strategy.

Area of Science:

  • Cardiovascular Biology
  • Endothelial Cell Biology
  • Metabolic Disease Research

Background:

  • Ras guanyl-releasing protein 2 (RASGRP2) regulates endothelial cell function.
  • The role of RASGRP2 in diabetes mellitus (DM)-related atherosclerosis (AS) progression is not well understood.

Purpose of the Study:

  • To investigate the role of RASGRP2 in high-glucose and oxidized low-density lipoprotein-induced human cardiac microvascular endothelial cell (HCMEC) dysfunction.
  • To explore the potential therapeutic strategies targeting the RASGRP2 pathway for DM-related AS.

Main Methods:

  • HCMECs were treated with high glucose (HG) and oxidized low-density lipoprotein (oxLDL).
  • RASGRP2 and NEDD4L expression, protein interactions, and ubiquitination were analyzed.
  • Cellular functions including viability, apoptosis, migration, and angiogenesis were assessed.
  • Exosomes derived from RASGRP2-overexpressing adipose-derived stem cells (ADMSCs) were utilized.

Main Results:

  • RASGRP2 expression was reduced in HG + oxLDL-treated HCMECs.
  • RASGRP2 overexpression improved endothelial cell function, inhibiting permeability and apoptosis while promoting viability, migration, and angiogenesis.
  • NEDD4L interacted with RASGRP2, promoting its degradation.
  • RASGRP2-overexpressing ADMSC-derived exosomes ameliorated endothelial cell dysfunction.

Conclusions:

  • The NEDD4L/RASGRP2 axis plays a critical role in regulating endothelial cell function in the context of DM-related AS.
  • Targeting the NEDD4L/RASGRP2 pathway or utilizing RASGRP2-modified ADMSC-exosomes represents a promising therapeutic approach for DM-related AS.
Keywords:
ADMSC-ExoAtherosclerosisDiabetes mellitusNEDD4LRASGRP2

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