Myocardial rhythm-mediated lipid metabolic dysfunction participates in adverse cardiac remodeling in offspring...

Adverse pregnancy air pollution exposure is associated with abnormal cardiovascular development and function in early life. However, the effects of maternal inhalation exposure to PM2.5 on cardiac dysfunction and related molecular mechanisms in offspring remain poorly understood. Proteomic analysis revealed that circadian rhythms regulate lipid homeostasis, with their disruption contributing to adverse cardiac remodeling in PM2.5-exposed F1 offspring. The cardiac circadian locomotor output cycles kaput (CLOCK) protein emerged as a key regulator of rhythmic fatty acid metabolic pathways in the heart. Perilipin 1 (PLIN1), a lipid droplet-associated protein, was strongly influenced by CLOCK, impeding fatty acid transfer from lipid droplets to mitochondria and leading to lipid droplet accumulation. Additionally, acyl-coenzyme A thioesterase 1 (ACOT1) displayed diurnal rhythms, sensitizing cardiomyocytes to docosahexaenoic acid (C22:6N3) and stearic acid (C18:0) in PM2.5-exposed F1 offspring. In the absence of cardiac CLOCK, forced expression of ACOT1 or PLIN1 enhanced lipid droplet metabolism, reduced abnormal lipid composition, and alleviated myocardial hypertrophy in PM2.5 F1 offspring. These findings indicate that circadian rhythm-regulated lipid dysfunction is a key mechanism underlying adverse cardiac remodeling in offspring exposed to PM2.5 during conception.