Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
Departamento de Química Analítica y Fisicoquímica, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Universidad de Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina.
Basic Res Cardiol. 2019 Aug 19;114(5):38. doi: 10.1007/s00395-019-0745-y.
There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1β mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.
目前人们已经意识到线粒体功能障碍在全身炎症综合征（尤其是脓毒症和内毒素血症）中心脏功能障碍发展中的核心作用。本研究旨在阐明指导全身炎症损伤严重程度与线粒体功能之间联系的机制，分析其对心脏功能（尤其是心脏收缩状态）的影响。雌性 Sprague-Dawley 大鼠接受低水平内毒素血症（腹腔注射 LPS 0.5mg/kg 体重）和严重内毒素血症（腹腔注射 LPS 8mg/kg 体重）处理 6h。随着内毒素血症严重程度的增加，血液中 NO 以及心脏 TNF-α 和 IL-1βmRNA 的含量增加。仅在严重内毒素血症时观察到心脏舒张功能改变，尽管在两种处理方式下，心脏收缩和舒张储备功能均受损，以应对工作超负荷。心脏超微结构显示两种内毒素血症程度均出现肌原纤维结构取向紊乱，但仅在严重内毒素血症时观察到线粒体肿胀和嵴断裂。线粒体 ATP 产生、耗氧量和内膜电位的降低与血液 NO 水平和线粒体蛋白硝化有关，导致 ATP 供应减少和收缩状态受损。NOS 抑制剂 L-NAME 或 NO 清除剂 c-PTIO 的共同处理导致观察到线粒体生物能状态取决于炎症损伤的程度，主要由血液 NO 水平决定。阐明脓毒症和内毒素血症发病机制可以提高对病理学的认识，并为新的治疗靶点提供新的思路。
