Oxygen sensors mediated HIF-1α accumulation and translocation: A pivotal mechanism of fine particles-exacerbated myocardial hypoxia injury

Epidemiological studies have demonstrated a strong association of ambient fine particulate matter (PM_2.5) exposure with the increasing mortality by ischemic heart disease (IHD), but the involved mechanisms remain poorly understood. Herein, we found that the chronic exposure of real ambient PM_2.5 led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM_2.5-induced HIF-1α accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1α-mediated energy metabolism remodeling from β-oxidation to glycolysis had a critical role in the PM_2.5-increased myocardial hypoxia injury. The in-depth analysis delineated that PM_2.5 exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1α and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1α. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM_2.5, resulting in the enhanced translocation of HIF-1α to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1α stabilization and translocation in PM-exacerbated myocardial hypoxia injury, we suggest this adds significantly to understanding the mechanisms of haze particles-caused burden of Cardiovascular Disease.