Targeting the endothelial clock to treat perioperative myocardial ischemia

靶向内皮时钟治疗围手术期心肌缺血

基本信息

批准号：
10705355
负责人：
Tobias Eckle
金额：
$ 38.28万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705355
关键词：
ANGPTL4 gene Acute Address Apoptosis Attenuated Binding Blood Vessels Cadherins Cardiac Cardiac Myocytes Cardiovascular system Cause of Death Cells Circadian Rhythms Clinical Trials Darkness Data Edema Endothelial Cells Endothelium Enhancers Environment Event Flavonoids Follow-Up Studies Functional disorder Future Gene Expression Gene Expression Regulation Genes Goals Heart Housing Human Infarction Injury Investigation Knockout Mice Knowledge Light Mediating Mitochondria Mus Myocardial Myocardial Ischemia Myocardial Reperfusion Myocardium Operative Surgical Procedures Pathway interactions Patients Perioperative Pharmaceutical Preparations Pharmacology Pharmacotherapy Phototherapy Plasma Promoter Regions Proteins Protocols documentation Recombinants Reperfusion Injury Reperfusion Therapy Research Respiration Role Signal Transduction Therapeutic Therapeutic Use Study Tight Junctions Time Tissues Up-Regulation base blind cardioprotection circadian clinically significant design endothelial dysfunction genome-wide hypoxia inducible factor 1 improved improved functioning in vivo insight knock-down mortality mouse model myocardial damage myocardial injury nobiletin novel novel therapeutics preconditioning prevent response therapeutic target tissue injury whole genome

项目摘要

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.

心肌缺血（MI）是全球死亡的主要原因之一。目前，的主要疗法急性MI仍然是早期的血运重建。但是，血运重建后的再灌注损伤是心肌损伤的重要原因。实际上，患者的1年死亡率高达42％周期性MI后进行血运重建。虽然内皮损害已被认为是造成心肌伤害的关键贡献者，尚未建立内皮保护策略。最近，我们开创了引起光的昼夜节律蛋白周期2（PER2）的新作用。防止Mi。调查针对目标和操纵PER2功能的光曝光策略显示在一个星期内而不是环境光条件下，将老鼠的饲养小鼠（14h灯：10h黑暗，黑暗， 10,000 lux，带有紫外线过滤器的全光谱）介导了鲁棒的心脏保护。作为基本机制，我们发现强烈的光增强了心脏PER2的昼夜节律放大器。出乎意料的是，随后研究表明，PER2的“振幅增强”建立了心脏保护和缺氧诱导因子1 alpha（HIF1A） - 相似的信号传导环境。昼夜节律放大器在不同环境中，增强已被视为一种受保护的机制，目前正在激烈的投资。但是，基本机制尚不清楚。整个基因组阵列强烈的光引起的基因调节发现了强烈的光线更新了HIF1A调节和内皮保护性血管生成素样4（Angptl4）蛋白质中的蛋白质。这个发现指的是在光吸收的心脏保护中表达PER2的内皮作用。确实，将小鼠与 per2的内皮特异性缺失，我们证明了光引起的心脏保护完全废除。此外，强烈的光预处理显着改善了内皮屏障功能心肌缺血，特有内皮PER2。因此，我们假设该放大器通过诱导HIF1A-engptl4的诱导来增强内皮PER2的扩增可提高血管完整性 MI中的心肌功能。为了解决这个问题，我们设计了三个具体目标：1。将吸毒的PER2定义为 MI中的内皮内皮囊保护策略，2。研究药物诱导HIF1A增加昼夜节律振幅并克服PER2缺乏症，3。研究内皮angptl4作为下游目标强烈的光引起心脏保护。这些研究的主要目的是表征可以是新型的，基于光的基于光的治疗靶标的进行身体修饰，并且在心脏保护中的强烈轻度处理也一样有效。经过调查新型内皮靶向策略，该提案有望确定新的高影响力可以有效地用于预防或在接受大手术的患者中减弱心肌的缺血组织损伤。