image: TCC exposure interferes with NO balance by altering arginine metabolism in cardiac organoid endothelial cells. As the dose increases, ROS production and iNOS activation lead to nitrosative stress and inflammation in endothelial cells, causing endothelial dysfunction and ultimately promoting cardiac organoids myocardial hypertrophy.
Credit: ©Science China Press
Heart failure is the terminal stage of various cardiovascular diseases, usually characterized by pathological myocardial hypertrophy. So far, the pathogenesis of heart failure is not fully understood. The global burden of cardiovascular disease and epidemiological evidence indicate that in addition to traditional risk factors such as genetic inheritance and hypertension, exposure to exogenous environmental pollutants is a new risk factor. In recent years, the use of antimicrobials has increased, resulting in more exposure of these substances to humans, raising concerns about potential risks to human and environmental health.
Triclocarban (3,4,4′-trichlorocarbanilide, TCC) is a broad-spectrum antibacterial agent commonly used in personal care products such as antibacterial soaps, detergents, toothpaste, and cosmetics. Unfortunately, due to its widespread use, TCC has become one of the top ten most common water pollutants globally, and it is present in the atmosphere, soil, and aquatic sediments. Especially during the post-COVID-19 pandemic era, antibacterial agents such as triclosan (TCS) and TCC have reached alarming levels in the environment. Due to its high lipophilicity and slow environmental degradation rate, TCC can accumulate in the environment and be absorbed by biological organisms. Recently, a study confirmed the association of exposure to antimicrobial agents TCC with coronary heart disease in humans. An animal study in mice also suggests TCC toxicity to the heart. However, the exact impact of TCC environmental exposure on human cardiovascular health and the underlying mechanisms remain unknown.
To better simulate the pathophysiological complexity of the human heart and reduce the reliance on animal experiments, human cardiac organoids (hCOs) from human induced pluripotent stem cells (hiPSCs) were used as a research model to explore the effects and mechanisms of TCC exposure at environmentally relevant doses (1, 2, 5 μmol/L). hCOs closely model human fetal cardiac development and produce main cardiac cell lineages, which are suitable for cardiac disease models. The authors found that exposure to environmental contaminant antimicrobial agent TCC can induce hypertrophy and metabolic remodeling of hCOs, and confirmed the early promoting role of endothelial cell metabolism in pathological cardiac hypertrophy, with doses that induce changes in endothelial metabolism preceding myocardial injury. Mechanistically, TCC exposure interferes with NO balance by altering arginine metabolism in cardiac organoid endothelial cells. As the dose increases, ROS production and iNOS activation lead to nitrosative stress and inflammation in endothelial cells, causing endothelial dysfunction and ultimately promoting cardiac organoids myocardial hypertrophy. These results suggest that endothelial arginine metabolism pathway and nitrosative stress may be a new treatment target for myocardial hypertrophy.
Journal
Science Bulletin