Effects of Arsenic-induced Diabetic Vascular Diseases through Mitogen-activated Protein Kinase Signaling Pathway: <i>In vitro</i> and <i>In vivo</i> Studies

Abstract

Arsenic (As) is an environmental pollutant that causes endocrine disruption. Diabetes increases the risk of Blackfoot disease, which is a peripheral artery disease caused by chronic exposure to As through drinking water in Taiwan and Bangladesh; however, the mechanism underlying this increased risk remains unclear. Therefore, in this study, we aimed to investigate the mechanisms underlying vascular damage in hyperglycemic conditions caused by As exposure using in vivo and in vitro studies. We utilized an animal model of streptozotocin-induced diabetes that was exposed to As through drinking water for 8 weeks. Subsequently, blood and organ samples of the animals were collected for follow-up analysis. Further, we cultured endothelial cells that were treated with As treatment in glucose condition and detected their biomarkers. The findings revealed that both the diabetes and diabetes + As groups exhibited insulin resistance, weight gain, and increased plasma triglyceride and total cholesterol levels. The diabetes + As group had lower antioxidant activity, which caused the arteries to exhibit prominent luminal narrowing with increased thickness. In vivo study revealed that glucose + As group-induced cell cycle arrest, a 98.80% increase in reactive oxygen species (ROS) levels, and decreased cell viability and mitochondrial membrane potential (MMP). However, in glucose + As group, treatment with SP600125 and U10126 treatment decreased ROS production by 80.5% and 84%, respectively, and restored MMP and cell viability. The glucose-regulated protein 78 level increased in the As as well as glucose + As groups. Our findings demonstrate that As exacerbates vascular damage in individuals with diabetes and its associated complications through the activation of the mitogen-activated protein kinase signaling pathway.