Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia
Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia
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DOI：
10.1096/fj.06-6349com
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Terzic, Andre
中科院分区：
文献类型：
--
作者：
Kane, Garvan C.;Lam, Chen-Fuh;Terzic, Andre
败血症是对感染的全身性炎症反应，对身体适应有很高的要求，心血管反应是结果的关键决定因素。在脓毒症综合征的情况下，确保心脏耐受的稳态因素尚不清楚。这里，在大肠杆菌脂多糖（LPS）内毒素攻击引起的急性感染性休克模型中，敲除编码血管Kir6.1 KATP通道孔的KCNJ8基因易导致早期和严重的生存劣势。这种应激反应细胞代谢传感器的破坏引起的过度易感性与心脏活动的进行性恶化、缺血性心肌损伤和收缩功能障碍有关。KCNJ8的缺失削弱了冠状血管对细胞因子或代谢介导的血管舒张的反应性，这是支持野生型（WT）心肌灌注所必需的，在Kir6.1基因敲除中造成适应性反应的缺陷。应用KATP通道开启剂药物可改善内毒素WT的生存，但对Kir6.1基因敲除没有影响。在致死性内毒素血症中，需要恢复冠状血管的扩张能力来挽救Kir6.1基因敲除表型并扭转生存劣势。因此，含有kir6.1的KATP通道通过将血管反应性与代谢需求耦合，为内毒素休克中心血管耐受性提供了重要的反馈元素。
Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 KATP channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress- responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a KATP channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing KATP channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.