Endogenous Activation of Mitochondrial KATP Channels Protects Human Failing Myocardium From Hydroxyl Radical–Induced Stunning
Endogenous Activation of Mitochondrial KATP Channels Protects Human Failing Myocardium From Hydroxyl Radical–Induced Stunning
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DOI：
10.1161/circresaha.109.206359
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发表时间：
2009-10
影响因子：
20.1
通讯作者：
C. Maack;E. Dabew;M. Hohl;H. Schäfers;M. Böhm
中科院分区：
文献类型：
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作者：
C. Maack;E. Dabew;M. Hohl;H. Schäfers;M. Böhm
理由：缺血心肌再灌注时，羟基自由基（&OV0635；H）的爆发引起收缩功能障碍（“心肌昏迷”），&OV0635；心肌梗死后患者血浆中H的含量可预测心衰的发展。&OV0635；心衰患者心肌功能的变化；然而，从未被评估过。此外，尽管atp依赖的K+通道（KATP通道）在缺血/再灌注（“缺血预处理”）期间参与心肌保护，但它们在心力衰竭中的作用几乎没有被阐明。目的：探讨&OV0635；H对人类衰竭心肌心肌收缩功能的影响，并阐明KATP通道在这种反应中的作用。方法与结果：非衰竭心脏离体左室小梁，&OV0635；H（由Fe3+-硝基三乙酸和H2O2产生）引起了大量的收缩和舒张功能障碍，而在衰竭心肌中，几乎没有休克。虽然在衰竭心肌中，肌层KATP通道（Kir6.2/SUR2）的蛋白表达上调约2倍，但在&OV0635；H存在下，用HMR-1098阻断它们并不会损害收缩功能。相反，当阻断线粒体KATP通道时，&OV0635；H暴露（伴有5-HD），衰竭心肌发生收缩功能障碍的程度与&OV0635；无KATP通道阻断的非衰竭心肌h致休克。结论：人衰竭左心室心肌耐药&OV0635；h诱导的休克，这种抗性与推测的线粒体KATP通道的内源性激活有关。鉴于某些同样阻断线粒体KATP通道的磺脲类药物（如格列本脲）经常用于糖尿病的治疗，我们的研究结果表明，在心力衰竭和糖尿病患者中，这些药物可能会损害缺血/再灌注时的左心室功能。
Rationale: During reperfusion of ischemic myocardium, a burst of hydroxyl radicals (&OV0635;H) induces contractile dysfunction (“myocardial stunning”), and &OV0635;H in the plasma of patients after myocardial infarction predict the development of heart failure. The effects of &OV0635;H on myocardial function in patients with heart failure; however, have never been assessed. Furthermore, although ATP-dependent K+ channels (KATP channels) are implicated in myocardial protection during ischemia/reperfusion (“ischemic preconditioning”), their role in heart failure has hardly been elucidated. Objective: To investigate the effects of &OV0635;H on cardiac contractile function in human failing myocardium, and to clarify the role of KATP channels during this response. Methods and Results: In isolated left ventricular trabeculae of nonfailing hearts, &OV0635;H (produced by Fe3+-nitrilotriacetic acid and H2O2) induced substantial systolic and diastolic dysfunction, whereas in failing myocardium, stunning was virtually absent. Although in failing myocardium, protein expression of sarcolemmal KATP channels (Kir6.2/SUR2) was ≈2-fold upregulated, their blockade with HMR-1098 did not impair contractile function in the presence of &OV0635;H. In contrast, when blocking mitochondrial KATP channels during &OV0635;H exposure (with 5-HD), failing myocardium developed contractile dysfunction to a degree that was comparable to &OV0635;H-induced stunning in nonfailing myocardium without KATP channel blockade. Conclusions: Human failing left ventricular myocardium is resistant to &OV0635;H-induced stunning, and this resistance is related to endogenous activation of putative mitochondrial KATP channels. Given that certain sulfonylurea drugs that also block mitochondrial KATP channels (eg, glibenclamide) are frequently used for the treatment of diabetes, our results imply that in patients with heart failure and diabetes, these drugs may impair left ventricular function during ischemia/reperfusion.