Trigonelline prevents high-glucose-induced endothelial-to-mesenchymal transition, oxidative stress, mitochondrial dysfunction, and impaired angiogenic activity in human endothelial EA.hy926 cells

• Published in: Biomedicine & pharmacotherapy 2024-10, Vol.179, p.117320, Article 117320
• Main Authors: Peerapen, Paleerath, Boonmark, Wanida, Chantarasaka, Suwichaya, Thongboonkerd, Visith
• Format: Article
• Language: English
• Subjects: Angiogenesis; Diabetes; EndMT; Mitochondria; Oxidized proteins; Proteomics; Therapeutics
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117320

Trigonelline (TRIG) is a natural compound in an alkaloid family found in diverse plants. This compound exerts anti-inflammatory, anti-allergic, anti-oxidative and anti-fibrotic activities in several disease models. However, its beneficial role in endothelial injury, especially induced by diabetes, is unclear. We, therefore, evaluated the effects of TRIG on the cellular proteome of human endothelial (EA.hy926) cells followed by functional validation in high-glucose (HG)-induced endothelial deteriorations. Label-free quantification using nanoLC-ESI-Qq-TOF MS/MS revealed 40 downregulated and 29 upregulated proteins induced by TRIG. Functional enrichment analysis using DAVID and REVIGO tools suggested the involvement of these altered proteins in several biological processes and molecular functions, particularly cell-cell adhesion, ATP metabolic process, cell redox homeostasis, cadherin binding, and ATP hydrolysis activity. Experimental validation showed that HG triggered endothelial-to-mesenchymal transition (EndMT) (as demonstrated by increased spindle index and mesenchymal markers, i.e., fibronectin and vimentin, and decreased endothelial markers, i.e., PECAM-1 and VE-cadherin), increased oxidized proteins, and reduced intracellular ATP, active mitochondria, endothelial tube/mesh formation and VEGF secretion. However, TRIG successfully abolished all these defects induced by HG. These data indicate that TRIG prevents HG-induced EndMT, oxidative stress, mitochondrial dysfunction, and impaired angiogenic activity in human endothelial cells. [Display omitted] •Trigonelline (TRIG) significantly altered levels of 69 proteins in EA.hy926 cells.•The altered proteins were involved in many biological processes/molecular functions.•High-glucose (HG) triggered endothelial-to-mesenchymal transition (EndMT).•HG induced oxidative stress, mitochondrial dysfunction and impaired angiogenesis.•TRIG could prevent all these HG-induced defects in human endothelial cells.