Impact of nitric oxide synthase on myocardial dysfunction of sepsis

描述（由申请人提供）：感染性休克是一种复杂的综合征，通常由创伤和/或手术引起的严重感染引起，身体对微生物侵入的反应在美国每年夺去超过20万人的生命。虽然一些脓毒性休克患者最终死于多系统器官衰竭，但许多患者死于难治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，以进一步改善脓毒性休克患者的护理。本研究的总体目的是表征一氧化氮（NO）和NO合成酶3 （NOS3）在脓毒症相关心肌功能障碍中的作用。获资助的研究将有四个目的：(1)在模拟人类腹膜炎的小鼠脓毒症模型中表征NOS3对心肌功能障碍和存活的影响；(2)阐明心肌NOS3减轻脓毒症诱导的心肌氧化应激的机制；(3)研究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改变和心肌细胞舒张的影响。拟议的研究将利用转基因小鼠和两种互补的脓毒症小鼠模型，脂多糖诱导的休克和手术诱导的弥漫性腹膜炎。在转基因小鼠中的发现将使用包括NO供体化合物和黄嘌呤氧化还原酶抑制剂在内的药理学试剂来证实。将在完整动物、分离心肌细胞和剥皮肌丝的水平上评估心肌功能。本研究旨在确定NOS3在脓毒症期间对心脏氧化应激、心肌功能障碍和生存的影响。通过了解心脏NOS3在脓毒症中的作用，我们预计所提出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。

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.