Kane Garvan C, Lam Chen-Fuh, O'Cochlain Fearghas, Hodgson Denice M, Reyes Santiago, Liu Xiao-Ke, Miki Takashi, Seino Susumu, Katusic Zvonimir S, Terzic Andre
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
FASEB J. 2006 Nov;20(13):2271-80. doi: 10.1096/fj.06-6349com.
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 K(ATP) 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 K(ATP) 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 K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.
脓毒症是机体对感染的全身性炎症反应，对身体适应能力提出了很高要求，其中心血管反应是预后的关键决定因素。在脓毒症综合征背景下确保心脏耐受性的稳态机制尚不清楚。在此，在由大肠杆菌脂多糖（LPS）内毒素激发诱导的急性脓毒性休克模型中，编码血管Kir6.1 K(ATP)通道孔的KCNJ8基因敲除导致早期和严重的生存劣势。这种细胞代谢应激反应传感器的破坏所引发的过度易感性与心脏活动的逐渐恶化、缺血性心肌损伤和收缩功能障碍有关。KCNJ8基因缺失减弱了冠状动脉对细胞因子或代谢介导的血管舒张的反应性，而这种反应性对于野生型（WT）心肌灌注的支持是必需的，从而在Kir6.1基因敲除小鼠中造成适应性反应缺陷。应用K(ATP)通道开放剂药物可提高内毒素血症野生型小鼠的生存率，但对Kir6.1基因敲除小鼠无效。恢复冠状动脉的舒张能力对于挽救Kir6.1基因敲除小鼠的表型和逆转致死性内毒素血症中的生存劣势是必需的。因此，含Kir6.1的K(ATP)通道通过将血管反应性与代谢需求相耦合，为内毒素性休克中的心血管耐受性提供了一个重要的反馈机制。
