Dr. Ruan’s Research

Circadian Cardioprotection: BMAL1/HIF2A Complex and Co-target Amphiregulin

Myocardial ischemia-reperfusion injury (IRI) is one of the most important predictors of short- and long-term outcomes in surgical patients. Despite the improvement in cardioprotective strategies, the mortality, and morbidity associated with heart failure after myocardial ischemia are still substantial. Therefore, the search for novel therapies to prevent or treat perioperative myocardial IRI is still an area of intense investigation. Previous studies indicate that adverse cardiovascular events including perioperative myocardial injury follow a circadian pattern, with more severity in the morning hours. Therefore, manipulating the molecular situation of the heart to resemble that in the less injury phase might be an attractive and safer strategy if the mechanisms are further elucidated. The hypoxia-inducible factors (HIF1A and HIF2A) have emerged as critical oxygensensitive transcription factors, which orchestrate the body’s endogenous protective response to hypoxia including myocardial IRI. Preliminary studies indicate that the core circadian transcription factor BMAL1 could interact with HIF2A, and form a transcriptionally active complex that is critical in mediating circadian-dependent cardioprotection via rhythmic induction of its co-target AREG. With this research we will further explore the possibility that the crosstalk between the hypoxia signaling and circadian rhythm can function as a circadian-dependent protective strategy to reduce myocardial injury. Specific Aims: Aim 1. Study circadian-dependent transcription activation of BMAL1/HIF2A on AREG in vitro; Aim 2. Study circadian-dependent cardioprotection of BMAL1/HIF2A-AREG pathway during IRI in vivo. Additionally, pharmacologic studies will be pursued to target the circadian-dependent pathway BMAL1/HIF2A-AREG to establish a novel clock-targeting therapy for myocardial IRI by harnessing two endogenous protective pathways synergistically.