Gao Zhan, Sierra Ana, Zhu Zhiyong, Koganti Siva Rama Krishna, Subbotina Ekaterina, Maheshwari Ankit, Anderson Mark E, Zingman Leonid V, Hodgson-Zingman Denice M
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
François Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, United States of America.
PLoS One. 2016 Mar 10;11(3):e0151337. doi: 10.1371/journal.pone.0151337. eCollection 2016.
The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP) channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD) in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB) model of heart failure is coupled with a 35-40% reduction in surface expression of KATP channels compared to hearts from sham-operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild-type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of CaMKII-dependent downregulation of KATP channel expression as a mechanism for vulnerability to injury in failing hearts points to strategies targeting this interaction for potential preventives or treatments.
寻找治疗和预防心力衰竭的新方法是医学领域的一项重大挑战。三磷酸腺苷敏感性钾（KATP）通道长期以来一直与在应激状态下维持心肌功能和活力的能力相关。膜KATP通道的高表面表达可确保在应对代谢挑战时，动作电位持续时间（APD）迅速节能缩短，而降低表面KATP通道表达的细胞信号传导会减弱APD缩短，从而以牺牲能量效率为代价，换取更多的细胞钙内流和增加的收缩力。在健康心脏中，钙/钙调蛋白依赖性蛋白激酶II（CaMKII）使Kir6.2 KATP通道亚基磷酸化，启动一系列导致KATP通道内吞的反应。在此，与假手术小鼠的心脏相比，在心力衰竭的经主动脉缩窄（TAB）模型中，CaMKII的激活与KATP通道表面表达降低35 - 40%相关。在分离的心肌细胞中证实了KATP通道表达与CaMKII之间的联系，其中CaMKII的激活导致KATP通道电流下调。因此，与非衰竭心脏相比，衰竭心脏在缺氧或心率加快时单相APD的缩短减慢，这一现象先前已表明会导致氧消耗显著增加。即使在没有冠状动脉疾病的情况下，衰竭心肌也可能因代谢供需不匹配而进一步受到缺血损伤。与野生型心脏相比，在缺血预处理后，CaMKII抑制的心脏中缺血再灌注损伤有所减轻，而当心肌KATP通道表达缺失时，这一优势基本消失，这支持了CaMKII抑制在心力衰竭中的心肌保护作用可能主要由KATP通道介导。认识到CaMKII依赖性下调KATP通道表达是衰竭心脏易受损伤的一种机制，为潜在的预防或治疗策略指明了针对这种相互作用的方向。
