Anesthetic-Induced Cardiac Preconditioning

麻醉诱导的心脏预处理

• 批准号: 7666171
• 负责人: Zeljko J. Bosnjak
• 金额: $ 174.82万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666171
• 关键词: Anesthetic; Induced; Cardiac; Preconditioning

DESCRIPTION (provided by applicant): Similar to the powerful endogenous cardioprotective mechanism of ischemic preconditioning, anesthetic-induced preconditioning (APC) has emerged as an equally effective cardioprotective intervention with better risk-to-benefit ratio for the patient. During the current cycle of the Program Project we have identified key elements and mechanisms involved in APC. Central to cardioprotection is the knowledge we have gained regarding the regulation of mitochondrial function by volatile anesthetics. Given the fundamental role of mitochondria in myocardial energetics and oxidative stress, we believe that they are a promising target for protective strategies such as APC. In contrast, disease states resistant to APC (e.g. diabetes) contain fundamental disturbances of mitochondrial function. The central theme of this Program Project is to elucidate the molecular mechanisms underlying APC. Specifically, we hypothesize that attenuation of permeability transition (PT) pore opening after ischemia and reperfusion is central to many of the phenotypic differences observed after exposure to volatile anesthetics. This Program will consist of three interrelated research projects supported by two Cores. Project I (Warltier) will focus on defining the temporal sequence of activation of key cardioprotective proteins related to the regulation of NO¿ production via HIF1a-VEGF-NO¿ axis by volatile anesthetics. Disruption of these elements and their effect on sarcKATp channel activity, mitochondrial-derived ROS formation, and tissue and cell injury will be determined. Project II (Bosnjak) will elucidate mechanisms involved in volatile anesthetic-dependent modulation of PT pore opening, a critical end effector of APC. It will address several factors that are critical to the role of the PT pore in APC such as mitochondrial bioenergetics and its proteome and the contribution of sarcKATp channels. Computational models of mitochondrial bioenergetics will be used to test specific hypotheses related to the effects of volatile anesthetics. Project III (Kersten) will investigate mechanisms involved in the attenuation of APC in diabetic animals. It will exploit a novel rat model of type 2 diabetes in which we were able to selectively switch the mitochondrial genome to further dissect the role of mitochondria and eNOS-sensitive pathway during impaired APC. All three Projects will be supported by a Biochemical and Molecular Biology Core (Harder) and a Proteomics Core (Olivier). These Cores will provide state-ofthe- art techniques in gene silencing, real time PCR, mitochondrial proteome, cell cultures, mitochondrial function assays, confocal microscopy and pathology. This Program Project represents a comprehensive effort to leverage our existing infrastructure and programmatic experience in physiology, biophysics, genomics, proteomics, and computational biology to advance our understanding of the cellular and subcellular effects of anesthetics in organ protection. Our findings are likely to have a significant impact in the clinical use of volatile anesthetics.

描述（由申请人提供）：与强大的内源性缺血预处理心脏保护机制类似，麻醉诱导预处理（APC）已成为一种同样有效的心脏保护干预措施，对患者具有更好的风险-收益比。在当前的项目周期中，我们已经确定了APC中涉及的关键要素和机制。心脏保护的核心是我们通过挥发性麻醉剂获得的关于线粒体功能调节的知识。鉴于线粒体在心肌能量和氧化应激中的基本作用，我们认为它们是APC等保护策略的有希望的目标。相反，抗APC的疾病状态（如糖尿病）包含线粒体功能的基本紊乱。