Aldehyde dehydrogenase 2 protects human umbilical vein endothelial cells against oxidative damage and increases endothelial nitric oxide production to reverse nitroglycerin tolerance

Abstract

ABSTRACT. Medical nitroglycerin (glyceryl trinitrate, GTN) use is limited principally by tolerance typified by a decrease in nitric oxide (NO) produced by biotransformation. Such tolerance may lead to endothelial dysfunction by inducing oxidative stress. In vivo studies have demonstrated that aldehyde dehydrogenase 2 (ALDH2) plays important roles in GTN biotransformation and tolerance. Thus, modification of ALDH2 expression represents a potentially effective strategy to prevent and reverse GTN tolerance and endothelial dysfunction. In this study, a eukaryotic expression vector containing the ALDH2 gene was introduced into human umbilical vein endothelial cells (HUVECs) by liposome-mediated transfection. An indirect immunofluorescence assay showed that ALDH2 expression increased 24 h after transfection. Moreover, real-time polymerase chain reaction and western blotting revealed significantly higher ALDH2 mRNA and protein expression in the gene-transfected group than in the two control groups. GTN tolerance was induced by treating HUVECs with 10 mM GTN for 16 h + 10 min, which significantly decreased NO levels in control cells, but not in those transfected with ALDH2. Overexpression of ALDH2 increased cell survival against GTN-induced cytotoxicity and conferred protection from oxidative damage resulting from nitrate tolerance, accompanied by decreased production of intracellular reactive oxygen species and reduced expression of heme oxygenase 1. Furthermore, ALDH2 overexpression promoted Akt phosphorylation under GTN tolerance conditions. ALDH2 gene transfection can reverse and prevent tolerance to GTN through its bioactivation and protect against oxidative damage, preventing the development of endothelial dysfunction.

Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

“…ALDH2 protects against heat shock and is involved in the pathogenesis of sepsis (72). ALDH2 overexpression prevented acetaldehydeinduced cell injury and decreased apoptosis in ECs and oxidative stress-induced endothelial dysfunction (73)(74)(75). Alda-1 binds to ALDH2 and restores ALDH activity by acting as a structural chaperone (29).…”

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cognitive Dysfunction by Inhibition of Reactive Aldehydes Involving Upregulation of ALDH2

“…ALDH2 has the highest catalytic efficiency for oxidation of 4-HNE and MDA ( Yoval-Sanchez and Rodriguez-Zavala, 2012 ). ALDH2 functions as a protector against oxidative stress ( Gao et al, 2016 ; Hu et al, 2016b ). Many researchers reported that the levels of MDA and 4-HNE were found to increase in the brain of AD patients ( Khan et al, 2012 ; Zhou et al, 2013 ) and that a sufficient amount of active ALDH2 is needed to detoxify the increased reactive aldehydes that occur in neurodegenerative diseases ( Ohsawa et al, 2008 ).…”

Perspective of SGLT2i in the Treatment of Abdominal Aortic Aneurysms

“…cardiovascular system include acting as the bioactivating enzyme for nitroglycerin and inactivating enzyme for reactive aldehydes removal, which has a great impact on the development of endothelial dysfunction 64,65 (Fig. 1).…”

“…Firs, Alda-1 (ALDH2 activator) was shown to attenuate the progression of AAA in a murine model. 62 , 63 Its roles in the cardiovascular system include acting as the bioactivating enzyme for nitroglycerin and inactivating enzyme for reactive aldehydes removal, which has a great impact on the development of endothelial dysfunction 64 , 65 (Fig. 1 ).…”