ALDH2 and NFκB Activation Restores VEGFR2 Expression and Angiogenesis Impaired by 4-HNE in Coronary Endothelial Cells

Document Type

Article

Publication Date

1-1-2026

Publication Title

Cell biochemistry and function

Keywords

Aldehyde Dehydrogenase, Mitochondrial, Aldehydes, NF-kappa B, Animals, Vascular Endothelial Growth Factor Receptor-2, Mice, Endothelial Cells, Neovascularization, Physiologic, Cells, Cultured, Coronary Vessels, Signal Transduction, Angiogenesis, Benzamides, Benzodioxoles

Abstract

4-hydroxy-2-nonenal (4HNE), a reactive aldehyde produced during lipid peroxidation, reduces angiogenesis in cultured mouse coronary endothelial cells (MCECs). In our previous studies, we found that 4HNE lowers both mRNA and protein levels of vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of angiogenesis. Since VEGFR2 transcription is regulated by nuclear factor kappa B (NFκB)-a well-known transcription factor-and aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme that detoxifies 4HNE, we sought to investigate how the interaction between ALDH2, 4HNE, and NFκB and VEGFR2 affects angiogenesis. Given that coronary endothelial cell rarefaction contributes to cardiometabolic conditions such as heart failure with preserved ejection fraction (HFpEF), it is imperative to study the underlying signaling mechanisms regulating coronary angiogenesis. In this study, we hypothesized that activation of ALDH2 enhances NFκB signaling, thereby preventing the 4HNE-induced reduction in VEGFR2 expression and restoring angiogenesis. To test this, MCECs were treated with disulfiram (DSF; 2.5 μM), an ALDH2 inhibitor; Alda-1 (10 μM), an ALDH2 activator; and prostratin (10 μM), an NFκB activator, prior to 4HNE (75 μM) exposure. Prostratin treatment increased both cellular and nuclear levels of NFκB across all conditions. Alda-1 pretreatment significantly rescued 4HNE-induced impairment of angiogenesis (p <  0.005 vs. 4HNE), while prostratin further enhanced Alda-1's effects (p <  0.005 vs. Alda-1 alone). Alda-1 restored VEGFR2 levels suppressed by 4HNE, and this effect was further potentiated by prostratin (p <  0.0005 vs. Alda1). In conclusion, NFκB activation enhances the protective effect of ALDH2 against 4HNE-induced angiogenic dysfunction by restoring VEGFR2 expression.

Medical Subject Headings

Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; NF-kappa B; Animals; Vascular Endothelial Growth Factor Receptor-2; Mice; Endothelial Cells; Neovascularization, Physiologic; Cells, Cultured; Coronary Vessels; Signal Transduction; Angiogenesis; Benzamides; Benzodioxoles

PubMed ID

41566697

Volume

44

Issue

1

First Page

70169

Last Page

70169

Find It @ Sladen

Share

COinS