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 (PM2.5) 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 PM2.5 led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM2.5- induced HIF-1 alpha accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1 alpha-mediated energy metabolism remodeling from beta-oxidation to glycolysis had a critical role in the PM2.5-increased myocardial hypoxia injury. The in-depth analysis delineated that PM2.5 exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1 alpha and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1 alpha. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM2.5, resulting in the enhanced translocation of HIF-1 alpha to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1 alpha stabili-zation 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.

Automated summary

Exposure to ambient PM2.5 leads to the upregulation of HIF-1α protein in mouse myocardium, resulting in myocardial injury and hypertrophy. PM2.5-induced HIF-1α accumulation is responsible for the promotion of myocardial hypoxia injury.