Targeting the endothelial clock to treat perioperative myocardial ischemia

心肌缺血（MI）是全球主要的死亡原因之一。目前，主要的治疗方法是 急性心肌梗死仍需早期血运重建。然而，血运重建后的再灌注损伤是一个重要的因素。 心肌损伤的重要原因。事实上，患者的1年死亡率高达42%， 在围手术期心肌梗死后接受血运重建。虽然内皮损伤已被认为是 心肌IR损伤的关键贡献者，尚未建立内皮保护策略。 我们最近开创了光诱导昼夜节律蛋白周期2（PER 2）在糖尿病中的新作用。 保护MI。针对和操纵PER 2功能的曝光策略的研究揭示了 将小鼠置于强光而非环境光条件下一周（14小时光照：10小时黑暗， 10，000 LUX，全光谱，带紫外线过滤器）介导强大的心脏保护作用。作为潜在机制，我们 发现强光增强了心脏PER 2的昼夜节律幅度。没想到，随后 研究表明，PER 2的这种“振幅增强”建立了心脏保护和缺氧， 诱导因子1 α（HIF 1A）类似的信号环境在未受伤的心脏。昼夜节律振幅 增强在不同的环境中被认为是一种保护机制，目前正在研究中。 紧张的调查。然而，其基本机制尚未得到很好的理解。全基因组阵列 强光诱导基因调控揭示了强光上调HIF 1A调节的， 内皮保护性血管生成素样4（ANGPTL 4）蛋白在未受伤的心脏。这一发现指出， 内皮细胞表达的PER 2在光诱导的心脏保护中的关键作用。事实上，使用小鼠， 内皮特异性缺失Per 2，我们证明光诱导的心脏保护作用完全是 废除此外，强光预处理显著改善了内皮屏障功能， 心肌缺血，这是内皮PER 2特异性的。因此，我们假设振幅 内皮PER 2的扩增通过诱导HIF 1A-ANGPTL 4增强血管完整性， MI时的心肌功能。为了解决这个问题，我们设计了三个具体目标：1。将药物引起的PER 2定义为 MI中的内皮屏障保护策略，2.研究药物诱导HIF 1A增加昼夜节律 振幅和克服Per 2缺陷，3.研究内皮ANGPTL 4作为下游靶点 强光对心脏有保护作用。 这些研究的主要目标是表征新的，基于光的治疗靶点， 在心脏保护方面与强光治疗一样有效。通过 研究新的内皮靶向策略，该提案有望确定新的，高影响力的， 缺血后心肌保护的治疗方法，可有效地用于预防或 减轻接受大手术的患者的心肌缺血性组织损伤。

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.