The cellular function and molecular mechanism of formaldehyde in cardiovascular disease and heart development

Abstract

As a common air pollutant, formaldehyde is widely present in nature, industrial production and consumer products. Endogenous formaldehyde is mainly produced through the oxidative deamination of methylamine catalysed by semicarbazide-sensitive amine oxidase (SSAO) and is ubiquitous in human body fluids, tissues and cells. Vascular endothelial cells and smooth muscle cells are rich in this formaldehyde-producing enzyme and are easily damaged owing to consequent cytotoxicity. Consistent with this, increasing evidence suggests that the cardiovascular system and stages of heart development are also susceptible to the harmful effects of formaldehyde. Exposure to formaldehyde from different sources can induce heart disease such as arrhythmia, myocardial infarction (MI), heart failure (HF) and atherosclerosis (AS). In particular, long-term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations than long-term exposure to low concentrations of formaldehyde. Specifically, the ability of mouse embryos to effect formaldehyde clearance is far lower than that of the rat embryos, more readily allowing its accumulation. Formaldehyde may also exert toxic effects on heart development by inducing oxidative stress and cardiomyocyte apoptosis. This review focuses on the current progress in understanding the influence and underlying mechanisms of formaldehyde on cardiovascular disease and heart development.

Keywords: atherosclerosis; cardiovascular disease; formaldehyde; heart development; semicarbazide-sensitive amine oxidase.

FIGURE 1

The mechanism of formaldehyde in cardiovascular disease. In the infarcted myocardium, there is MPO released by leukocytes, which can change the oxidation α‐amino produce formaldehyde. For example, MPO‐oxidation products such as glycine (formaldehyde) and threonine (acrolein) exhibit relatively high cytotoxicity. SSAP/VAP1 expressed on the surface of endothelial cells can mediate leukocyte rolling and adhesion in the leukocyte extravasation cascade. These potential mechanisms of action may accelerate the occurrence and development of MI. In the heart, direct contact of formaldehyde with SN or other cardiac conduction systems in different ways may cause SSS or other arrhythmias. Racemic histamine may repolarize the K⁺ current by promoting the influx of Ca²⁺ and Na⁺ to improve arrhythmia caused by formaldehyde. Cigarette smoke contains a large number of reactive aldehydes such as formaldehyde, acetaldehyde and acrolein, which can weaken the reverse transport of cholesterol mediated by HDL by inactivate LCAT and promote the formation of AS. The activity of SSAO in the serum of T1DM patients and T2DM patients is determined by radio‐enzymatic assay. The formaldehyde or H₂O₂ generated by SSAO through oxidative deamination can induce or aggravate endothelial cell damage and accelerate the development and severity of diabetic complications such as AS. The formaldehyde present in the air or the formaldehyde produced by SSAO oxidative deamination in the human body may be potentially inducible to stroke. Elevated SSAO activity can be detected in the plasma of patients with congestive heart failure. The higher SSAO activity in patient plasma, the higher the risk of death. HDL, high‐density lipoprotein; LCAT, cholesterol acyltransferase; MPO, myeloperoxidase; SN, sinus node; SSAO, semicarbazide‐sensitive amine oxidase;T1DM, types 1 diabetes mellitus; T2DM, 2 diabetes mellitus

FIGURE 2

The mechanism of formaldehyde in AS. A, Low‐dose formaldehyde (0.1 mM) can enhance endothelial cell proliferation and reduce apoptotic activity, 1.0 mM formaldehyde can enhance endothelial cell apoptosis and reduce mitosis in a moderate manner. However, high doses of formaldehyde (10.0 mM) can cause strong damage to endothelial cells. Different concentrations of formaldehyde can cause vascular sclerosis and endothelial damage leading to AS. B, SSAO/VAP‐1 mediates the oxidative deamination of methylamine to form formaldehyde and induces VSMC cell apoptosis. SSAO:semicarbazide‐sensitive amine oxidase; VAP‐1,vascular adhesion protein‐1; VSMCs, Vascular Smooth Muscle Cells. C, AG can prevent formaldehyde‐induced B‐amyloid aggregation and eliminate formaldehyde by inhibiting SSAO, thereby reducing the occurrence and development of diabetic vascular complications (such as atherosclerosis). AG, aminoguanidine. D, Formaldehyde can combine with the amino group of lysin in the same or different proteins by interacting with the e‐amino group of lysine to form a Schiff base to further form a stable methylene bridge. Formaldehyde can also interact with amide groups to form unstable Schiff bases and hydroxymethyl groups between crosslinked proteins and DPCs. Moreover, formaldehyde‐induced DPC formation changes the conformation and function of DNA and may also mediate vascular sclerosis, which can damage the endothelium and become a potential risk factor for AS. SSAO‐mediated formaldehyde generation may be involved in the formation of vascular plaques. The continuous accumulation of formaldehyde concentration in the body may also cause damage to endothelial cells and lead to the occurrence of AS

FIGURE 3

Toxicity mechanism of formaldehyde to embryonic heart development. A, Methanol produced in the air or directly induced embryos with formaldehyde may metabolize methanol to formaldehyde through ADH1, ADH3 and catalase in the embryos, leading to abnormal embryonic heart development such as congenital heart disease. ADH1, alcohol dehydrogenase1; ADH3, formaldehyde dehydrogenase 3. B, Exposure to high doses of formaldehyde during pregnancy may induce oxidative stress in pregnant mice and offspring to produce excessive ROS, which decrease the activity of SOD and increases in MDA, leading to apoptosis of offspring cardiomyocytes. MDA, malondialdehyde; ROS, reactive oxygen species; SOD, superoxide dismutase