Glyoxal (GX), the smallest dialdehyde, is the most widely used retarding agent in the synthesis of chemicals, such as novel bio-adhesives for wood [
1‐
3], and is also found in the environment [
4]. In humans, a high dietary glycemic load leading to insulin resistance causes alterations in glucose and lipid metabolism, and results in the production of excess aldehydes, such as GX and methylglyoxal, which are associated with the progression of certain diseases, including cardiovascular disorders [
5,
6]. With respect to tissue dysfunction, GX has been implicated in the progression of several degenerative conditions, such as Alzheimer’s disease and diabetes mellitus, in which increased serotonin release from the cells stimulate serotonin-mediated intestinal motility [
7]. Furthermore, the consumption of high-carbohydrate diets might also induce the endogenous formation of GX [
6]. Regarding DNA damage and tumor growth, DNA duplexes can undergo intra- and inter-cross-linking damage through the formation of GX–guanine adducts [
8,
9]. Exposure to 0.1% GX was found to cause a significant increase in tumor size in the small intestines of male and female mice [
10]. GX can also trigger changes to erythrocytes; specifically, it induces the modification of arginine residues of HbA0-forming G-H1, which decreases free iron-mediated oxidative reactions. GX-derived G-H1-mediated changes in the structural and functional properties of the heme protein, observed in vivo, may be of clinical significance [
11]. Erythrocytes take up exogenous GX and convert it primarily to glycolate, and approximately 1% of this is converted to oxalate. This pathway of oxalate formation may be enhanced in diabetes and other diseases associated with increased oxidative stress [
12]. Glutathione (GSH), a reactive cysteine residue containing a tripeptide, is the major soluble antioxidant molecule in cells due to its abundance in the cytosol, nucleus, and mitochondrion [
13‐
16]. Thioredoxin-1 (Trx1) mainly acts by cleaving the disulfide bonds of oxidized proteins, thus affecting intracellular scavenging of oxidative stress. This action relies on cell survival, cell growth, and gene transcription [
17]. Finally, the enzymes involved in glycolysis are heavily modified by GX, which can significantly inhibit the activity of GAPDH, which can in turn contribute to the pathological processes by impairing glycolytic processes [
18].
The toxic effects of aldehydes include protein damage caused by the exposure of cells to endogenous and exogenous aldehydes, which leads to the formation of covalent adducts with proteins, leading to dysfunction. In addition, DNA damage, such as DNA double strand breaks (DSBs) [
19], DNA–protein crosslinks (DPCs), or DNA interstrand crosslinks (ICLs) [
20], occurs when a protein or DNA base in one strand undergoes further reactions with aldehyde–DNA base adducts in the opposite strand [
21]. The FANC pathway, which includes the complementation group A (FANCA), is the major underlying mechanism involved in the repair of ICLs induced by aldehydes [
19].
Previous studies have shown that aldehydes are independent risk factors for cardiovascular disease [
17‐
19]. For example, GX is associated with critical targets in the human aortic endothelial cells (HAECs), which are implicated in several cardiovascular diseases. GX is also involved in the development of abnormal structures and functions of the arteries, such as atherosclerosis [
5,
6]. The main objective of this study was to examine the damage-inducing effects of GX on HAECs and to provide novel insights into the molecular mechanisms that are perturbed by GX, which may, in turn, facilitate the development of new therapeutics and diagnostic markers for cardiovascular diseases.