Targeting the endothelial clock to treat perioperative myocardial ischemia

心肌缺血（MI）是世界范围内导致死亡的主要原因之一。目前，主要的治疗方法是

Myocardial ischemia (MI) is one of the leading causes of death worldwide. Currently, the mainstay therapy of acute MI remains early revascularization. However, reperfusion injury following revascularization is a significant cause of myocardial damage. In fact, 1-year mortality rates are as high as 42% in patients undergoing revascularization after perioperative MI. While endothelial damage has been recognized as a critical contributor to myocardial IR-injury, no endothelial-protective strategy has been established yet. We recently pioneered a novel role for the light elicited circadian rhythm protein Period 2 (PER2) in protection from MI. Investigation of light exposure strategies to target and manipulate PER2 function revealed that housing mice under intense instead of ambient light conditions for one week (14h light:10h darkness, 10,000 LUX, full-spectrum with UV filter) mediates robust cardioprotection. As the underlying mechanism, we discovered that intense light enhanced the circadian amplitude of cardiac PER2. Unexpectedly, subsequent studies revealed that this ‘amplitude enhancement’ of PER2 established a cardioprotective and hypoxia inducible factor 1 alpha (HIF1A)-similar signaling environment in the uninjured heart. Circadian amplitude enhancement has been implicated as a protective mechanism in different settings and is currently under intense investigation. However, the underlying mechanisms are not well understood. A whole-genome array on intense light elicited gene regulation uncovered that intense light upregulated the HIF1A-regulated and endothelial-protective Angiopoietin-like 4 (ANGPTL4) protein in the uninjured heart. This discovery pointed towards a critical role for endothelial expressed PER2 in light-elicited cardioprotection. Indeed, using mice with endothelial-specific deletion of Per2, we demonstrated that light elicited cardioprotection was completely abolished. Moreover, intense light pretreatment significantly improved endothelial barrier function following myocardial ischemia, which was endothelial PER2 specific. Therefore, we hypothesize that amplitude amplification of endothelial PER2 boosts vascular integrity via induction of HIF1A-ANGPTL4 which improves myocardial function in MI. To address this, we designed three specific aims: 1. Define drug-elicited PER2 as an endothelial-barrier-protective strategy in MI, 2. Study drug induced HIF1A to increase the circadian amplitude and to overcome Per2 deficiency, 3. Study endothelial ANGPTL4 as a downstream target of intense light elicited cardioprotection. The main goal of these studies is to characterize novel, light-based therapeutic targets that can be modified pharmacologically and are as effective as an intense light treatment in cardioprotection. By investigating novel endothelium-targeting strategies, this proposal promises to identify new, high-impact therapeutic approaches for post-ischemic myocardial protection that could effectively be used to prevent or attenuate ischemic tissue injury of the myocardium in patients undergoing major surgery.