Mechanisms of photobiomodulation in myocardial reperfusion injury

描述（由申请人提供）： 该提案的长期目标是确定涉及红光至近红外范围（630- 1，000 nm; NIR）的光的心脏保护作用的机制。我们的实验室已经发现，在冠状动脉闭塞30分钟后的再灌注点，将狗、兔和小鼠心肌短暂暴露于由发光二极管产生的670 nm波长的光（3分钟），导致梗死面积显著减小。此外，与缺血或药物后处理相比，近红外介导的心脏保护机制存在显著差异。这可能允许近红外用于疾病模型中的心脏保护，如糖尿病，其中药理学后处理已被证明是无效的。我们建议测试的总体假设，即近红外治疗心肌，立即延长缺血期后，涉及释放一氧化氮（NO）从血红素蛋白质。由此产生的，并且重要的是，NO的位点特异性释放靶向保护性信号传导途径和线粒体代谢。将使用三个特定目的来确定含有肌红蛋白、血红蛋白和/或细胞色素c氧化酶的NO对NIR在非糖尿病和糖尿病小鼠中的心脏保护作用的潜在贡献。具体目的我将研究NIR对糖尿病和非糖尿病小鼠的细胞和组织保存和功能以及线粒体生物能量学的影响，并将其与传统的NO供体进行比较。具体目标II将研究从血红素结合伙伴主要使用生物物理方法在无细胞，细胞和组织模型的再灌注损伤的NO释放。具体目标III将探索NO的来源，这在很大程度上是近红外线观察到的心脏保护作用的原因，并将近红外线的应用扩展到非侵入性或微创动物模型。在整个提案中，我们将利用市售的或我们从外部合作者处获得的相关鼠基因敲除。负责的近红外线的能力，以减轻缺血心肌在再灌注损伤的机制还没有得到表征，这项工作的结果将显着增加心血管生物学和光生物学领域。重要的是，由于其相对安全的特性，NIR用于再灌注损伤具有快速转化为临床的潜力。 公共卫生相关性： 项目叙述：缺血心肌的再灌注损伤在美国是一个重要的问题。已经确定了几种药理学药物来保护心脏免受再灌注损伤，但转化为临床环境产生了相互矛盾的结果。近红外光，单独或与其他药理学佐剂组合，可以提供一种独特的策略，以减轻在冠状动脉再灌注期间对缺血心肌发生的损伤。

DESCRIPTION (provided by applicant): The long term goal of this proposal is to identify those mechanisms involved in the cardioprotective effect of light in the red to near infrared range (630-1,000 nm; NIR). Our laboratory has found that brief exposure (3 min) of dog, rabbit and mouse myocardium to 670 nm wavelength light generated by a light-emitting diode at the point of reperfusion following a 30 minute coronary artery occlusion results in a significant reduction in infarct size. Moreover, striking differences in the mechanisms involved in NIR-mediated cardioprotection have been discovered compared to ischemic or pharmacological postconditioning. This may allow application of NIR for cardioprotection in disease models such as diabetes where pharmacological postconditioning has proven to be ineffective. We propose to test the overall hypothesis that NIR treatment of myocardium, immediately following a prolonged ischemic period, involves the release of nitric oxide (NO) from heme-containing proteins. The resulting, and, importantly, site-specific release of NO targets protective signaling pathways and mitochondrial metabolism. Three Specific Aims will be used to identify the potential contributions of NO containing myoglobin, hemoglobin and/or cytochrome c oxidase to the cardioprotective effect of NIR in the non-diabetic and diabetic mouse. Specific Aim I will investigate the effects of NIR on cellular and tissue preservation and function and on mitochondrial bioenergetics in the diabetic and non-diabetic mouse, and compare the effect with a conventional NO-donor. Specific Aim II will study the release of NO from heme-binding partners using mainly biophysical methodologies in cell-free, cellular and tissue models of reperfusion injury. Specific Aim III will explore the source of NO that is largely responsible for the observed cardioprotective effect of NIR and expand the application of NIR to a non- or minimally-invasive animal model. Throughout this proposal we will make use of relevant murine knockouts that are either commercially available or that we have secured from outside collaborators. The mechanisms responsible for the ability of NIR to attenuate the damage to ischemic myocardium during reperfusion have not been characterized and the results of this work will add significantly to the fields of cardiovascular biology and photobiology. Importantly, the use of NIR for reperfusion injury has the potential for rapid translation to the clinic given its relatively safe profile. PUBLIC HEALTH RELEVANCE: Project Narrative: Reperfusion injury of the ischemic myocardium represents a significant problem in the United States. Several pharmacological agents have been identified to protect the heart from reperfusion injury but translation to the clinical setting has yielded conflicting results. Near infrared light, alone or in combination with other pharmacological adjuvants could offer a unique strategy to mitigate the damage that occurs to the ischemic myocardium during reperfusion of the coronary artery.