Impact of nitric oxide synthase on myocardial dysfunction of sepsis

一氧化氮合酶对脓毒症心肌功能障碍的影响

基本信息

批准号：
7618495
负责人：
FUMITO ICHINOSE
金额：
$ 31.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-08 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7618495
关键词：
Animals Attenuated Calcium Cardiac Cardiac Myocytes Cardiovascular system Caring Cessation of life Clinical Trials Complex Critical Illness Development Diffuse Endotoxemia Functional disorder Grant Human Hypotension Infection Intensive Care Learning Life Lipopolysaccharides Mechanics Microfilaments Modeling Modification Molsidomine Mus Myocardial Myocardial dysfunction Myocardium NOS1 gene Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Operative Surgical Procedures Organ failure Oxidative Stress Pathogenesis Patient Care Patients Peripheral Resistance Peritonitis Phosphorylation Protein Isoforms Proteins Refractory Relaxation Research Role Sepsis Septic Shock Shock Skin Study Section Syndrome System Transgenes Trauma United States Xanthine Dehydrogenase cardiac depression human NOS3 protein improved in vivo indexing inhibitor/antagonist insight mortality mouse model novel therapeutics overexpression oxidoreductase inhibitor phospholamban prevent protein function response septic

项目摘要

DESCRIPTION (provided by applicant): Septic shock is a complex syndrome that results from serious infection often initiated by trauma and/or surgery and the body's response to microbiologic invation claims over 200,000 lives per year in the United States. While some patients with septic shock eventually succumb to multisystem organ failure, many die of refractory hypotension and cardiovascular collapse. A better understanding of the complex pathogenetic mechanisms leading to cardiovascular collapse is needed to further improve the care of patients with septic shock. The overall objective of the proposed research is to characterize the role of nitric oxide (NO) and NO synthase 3 (NOS3) in the myocardial dysfunction associated with sepsis. Studies supported by this grant will have four aims: (1) characterize the impact of NOS3 on myocardial dysfunction and survival in a murine sepsis model that closely mimics human peritonitis, (2) elucidate the mechanisms whereby cardiac NOS3 attenuates sepsis-induced myocardial oxidative stress, (3) examine the mechanisms responsible for the altered myofilament sensitivity to calcium during sepsis, and (4) assess the impact of NOS3 on sepsis- induced alteration of calcium handling protein and cardiomyocyte relaxation. Proposed studies will take advantage of genetically-modified mice and two complementary mouse models of sepsis, lipopolysaccharide-induced shock and surgically-induced diffuse peritonitis. Findings in genetically-modified mice will be confirmed using pharmacological agents including NO donor compound and xanthine oxidoreductase inhibitors. Myocardial function will be assessed at the levels of intact animal, isolated cardiomyocytes, and skinned-myofilaments. This proposal seeks to define largely unexplored impact of NOS3 on cardiac oxidative stress, myocardial dysfunction, and survival during sepsis. By understanding the role of cardiac NOS3 during sepsis, we anticipate that the proposed studies will provide important information leading to the development of new therapeutic strategies to improve the care of critically ill patients with myocardial dysfunction of sepsis.

描述（由申请人提供）：脓毒性休克是一种复杂的综合征，由通常由创伤和/或手术引发的严重感染以及身体对微生物感染的反应引起，在美国每年夺去超过 200,000 人的生命。虽然一些感染性休克患者最终死于多系统器官衰竭，但许多患者死于顽固性低血压和心血管衰竭。需要更好地了解导致心血管衰竭的复杂发病机制，以进一步改善感染性休克患者的护理。本研究的总体目标是确定一氧化氮 (NO) 和一氧化氮合酶 3 (NOS3) 在脓毒症相关心肌功能障碍中的作用。该资助支持的研究将有四个目标：（1）在高度模仿人类腹膜炎的小鼠脓毒症模型中描述 NOS3 对心肌功能障碍和生存的影响，（2）阐明心脏 NOS3 减轻脓毒症诱导的心肌氧化应激的机制，（3）检查脓毒症期间肌丝对钙敏感性改变的机制，（4）评估NOS3对脓毒症诱导的钙处理蛋白和心肌细胞松弛变化的影响。拟议的研究将利用转基因小鼠和两种互补的败血症、脂多糖诱导的休克和手术诱导的弥漫性腹膜炎小鼠模型。转基因小鼠的研究结果将通过包括 NO 供体化合物和黄嘌呤氧化还原酶抑制剂在内的药物得到证实。心肌功能将在完整动物、分离的心肌细胞和带皮肌丝的水平上进行评估。该提案旨在明确 NOS3 对脓毒症期间心脏氧化应激、心肌功能障碍和生存的影响，这些影响尚未被探索。通过了解心脏 NOS3 在脓毒症期间的作用，我们预计拟议的研究将为开发新的治疗策略提供重要信息，以改善脓毒症心肌功能障碍危重患者的护理。