Abstract: BACKGROUND: The development and progression of heart failure are closely related to abnormal activation of the neuroendocrine system. Studies have demonstrated that light exposure decreases dopamine levels in the rat brain, increases the activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus, and stimulates the release of corticotropin releasing factor. However, there is currently no direct evidence proving that light exposure induces heart failure.
Objective: To investigate the effect and molecular mechanism of light exposure on neurotransmitter release in heart failure model rats, and to conduct cytological verification.
Methods: (1) Animal experiment: Sprague-Dawley rats with heart failure were divided into model, light exposure model, and light exposure treatment groups, while shamsurgery rats were divided into light exposure control and blank groups, with six rats in each group. After 8-week experiment, enzyme linked immunosorbent assay was used to detect the effects of light exposure on serum levels of neurotransmitter and hormone in heart failure rats. Hematoxylin-eosin staining was used to detect pathological changes in the heart. Western blot assay was used to detect the regulatory effects of nuclear factor E2 related factor 2/heme oxidase 1/NADPH quinineoxidoreductase-1 signaling pathway. (2) Cell experiment: Mouse cardiomyocytes (HL-1 cells) were divided into blank, high-dose 5-hydroxytryptamine control (5-hydroxytryptamine 500 mg/mL), low-dose lipopolysaccharide (lipopolysaccharide 1 μg/mL), lipopolysaccharide + high-dose 5-hydroxytryptamine (5-hydroxytryptamine 500 mg/mL + lipopolysaccharide 1 μg/mL), ML385 (lipopolysaccharide 1 μg/mL + 5-hydroxytryptamine 500 mg/mL + nuclear factor E2 related factor 2 inhibitor ML385 2.5 μg/mL), and resveratrol (lipopolysaccharide 1 μg/mL + 5-hydroxytryptamine 500 mg/mL + 
nuclear factor E2 related factor 2 agonist resveratrol 30 μg/mL) groups. After 36-hour intervention, the effects of various intervention conditions on cell proliferation were investigated. Western blot assay was used to verify the effect of 5-hydroxytryptamine on nuclear factor E2 related factor 2/heme oxidase 1/NADPH quinineoxidoreductase-1 signaling axis in HL-1 cells.
Results and conclusion: (1) Animal experiment: Light exposure increases the serum levels of norepinephrine and 5-hydroxytryptamine in heart failure model rats, thereby exacerbating heart damage. Both light exposure model and model groups showed significant pathological damage to the myocardial tissue, including swelling, nuclear shrinkage, and the formation of vacuoles. However, the damage to myocardial cells in the light exposure treatment group was significantly alleviated. In the light exposure control group, the level of angiotensin converting enzyme 2 protein expression was lower than that in the blank group (P < 0.05), but higher than that in the model group (P < 0.05). Although Mas, c-fos, and heme oxygenase-1 expression levels were downregulated compared to the blank group, but these differences were not statistically significant (P > 0.05). In the light-exposed model group, the protein expression levels of angiotensin converting enzyme 2, Mas, nuclear factor E2 related factor 2, and heme oxygenase-1 were significantly downregulated compared to the blank group (P < 0.05). Compared with the light exposure model group, the expression level of proteins related to the nuclear factor E2 related factor 2/heme oxygenase-1/NADPH quinineoxidoreductase-1 signaling pathway was significantly upregulated in the light exposure treatment group (P < 0.05). (2) Cell experiments: 5-Hydroxytryptamine increased lipopolysaccharide-induced myocardial cell damage. This damage was associated with the inhibition of the nuclear factor E2 related factor 2/heme oxidase 1/NADPH quinineoxidoreductase-1 signaling pathway. Conclusion: Excessive light exposure may accelerate the progression of heart failure by regulating neurotransmitter composition, mediating the nuclear factor E2 related factor 2/heme oxidase 1/NADPH quinineoxidoreductase-1 signaling pathway.  

Key words: light exposure, heart failure, neurotransmitter, 5-hydroxytryptamine, myocardial cell injury, nuclear factor E2 related factor 2