Cardioprotection against endotoxins

对抗内毒素的心脏保护作用

• 批准号: 6769959
• 负责人: RUBEN MESTRIL
• 金额: $ 25.9万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769959
• 关键词: cardiac myocytes; cell morphology; cytoprotection; endotoxins; fluorescent dye /probe; genetically modified animals; heat shock proteins; heat stimulus; hemodynamics; laboratory mouse; laboratory rat; nitric oxide synthase; nuclear factor kappa beta; septic shock; tissue /cell culture; transfection; tumor necrosis factor alpha; video recording system

DESCRIPTION (provided by applicant): A number of studies have shown that rodents submitted to a mild whole body heat shock become resistant to a subsequent lethal dose of lipopolysaccharides (LPS). It is still unclear how a pre-heat treatment protects against endotoxins but one of the main results of a heat shock is the increased synthesis of a group of proteins known as the heat shock proteins (hsp). The hsp70 is the most abundant of these hsps and has been postulated to be the principal mediator of the observed protection against LPS. Since one of the majors consequences of endotoxemia is the induction of myocardial contractile dysfunction and hsp70 has been previously shown to protect against myocardial dysfunction due to infarction. We therefore propose to investigate the mechanism by which the hsp70 protects the myocardium during endotoxemia. Our preliminary results show that heat shocked isolated rat neonatal cardiomyocytes are tolerant to a subsequent exposure to LPS. In addition, cardiomyocytes infected with adenoviral vectors containing the hsp70 gene are also tolerant to endotoxin exposure in vitro. We also find that a transgenic mouse line overexpressing a hsp70 gene is more tolerant to endotoxemia than littermates that do not express the hsp70 transgene. The mechanism in which hsp70 renders the cardiomyocyte both in vitro and in vivo tolerant to endotoxemic injury would seem to involve a reduction in inducible nitric oxide synthase expression according to our preliminary results. We therefore propose to study in both isolated cardiomyocytes and the heart tissue of transgenic mice, the level of the mediators of endotoxin-induced cell injury: TNF-alpha, IL-1, nitric oxide (NO), inducible NO synthase and the transcription factor NFkB and how they are affected by the increased presence of hsp70. The proposed research project should clearly demonstrate if the sole presence of increased levels of hsp70 is protective against endotoxemia. This proposed study may open the way to harness the endogenous protective mechanisms in cardiomyocytes and to new innovative and effective therapies against the myocardial depression caused by endotoxins.

描述(由申请人提供)：许多研究表明，遭受轻度全身热休克的啮齿类动物对随后致命剂量的脂多糖(LPS)具有抵抗力。目前尚不清楚预热处理如何防止内毒素，但热休克的主要结果之一是增加了一组被称为热休克蛋白(HSP)的蛋白质的合成。HSP70是这些热休克蛋白中含量最丰富的，并被认为是观察到的对内毒素的保护作用的主要中介。由于内毒素血症的主要后果之一是诱导心肌收缩功能障碍，而HSP70先前已被证明可以预防因心肌梗死而导致的心肌功能障碍。因此，我们建议研究热休克蛋白70在内毒素血症时保护心肌的机制。我们的初步结果表明，热休克分离的新生大鼠心肌细胞对随后的内毒素暴露具有耐受性。此外，感染含有HSP70基因的腺病毒载体的心肌细胞在体外也能耐受内毒素。我们还发现，过度表达HSP70基因的转基因小鼠比不表达HSP70转基因的小鼠更耐受内毒素血症。根据我们的初步结果，HSP70使体外和体内心肌细胞对内毒素损伤耐受的机制似乎涉及诱导型一氧化氮合酶表达的减少。因此，我们建议在转基因小鼠的分离心肌细胞和心脏组织中研究内毒素诱导的细胞损伤的介体：肿瘤坏死因子-α、白介素1、一氧化氮(NO)、诱导型一氧化氮合酶和转录因子NFkB的水平，以及HSP70的存在对它们的影响。拟议的研究项目应该清楚地证明，HSP70水平升高的单独存在是否对内毒素血症具有保护作用。这项研究可能为利用心肌细胞的内源性保护机制以及对内毒素引起的心肌抑制的新的创新和有效的治疗方法开辟道路。