Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia.
Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia.
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DOI：
10.1161/circresaha.112.274308
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发表时间：
2013-01-18
影响因子：
20.1
通讯作者：
Zuurbier CJ
中科院分区：
文献类型：
--
作者：
Nederlof R;Xie C;Eerbeek O;Koeman A;Milstein DM;Hollmann MW;Mik EG;Warley A;Southworth R;Akar FG;Zuurbier CJ
我们已经证明，使用低剂量（200 nM）TAT-HKII将HKII与完整心脏中的线粒体部分解离可防止缺血预处理（IPC）的心脏保护作用，而高剂量（10 μM）TAT-HKII给药可导致快速心肌功能障碍、线粒体去极化和解体。在本期《循环研究》中，Pasdois等人认为TAT-HKII给药对心脏功能的有害影响可能是由于血管收缩和随后的缺血。研究血管功能改变和随后的缺血是否重现了TAT-HKII在完整心肌中的有害作用。使用各种补充技术，包括线粒体膜电位（Δ Km）成像、高分辨率光学动作电位（AP）绘图、乳酸产生分析、NADH荧光显色、乳酸脱氢酶（LDH）释放和电子显微镜，我们提供了直接证据，驳斥了大剂量TAT-HKII肽给药导致急性心肌功能障碍是血管功能受损的结果的观点。此外，我们证明，低剂量的TAT-HKII治疗，消除IPC的保护作用，是不相关的缺血或缺血损伤。我们的研究结果挑战的概念，TAT-HKII的影响是由于受损的血管功能和随后的缺血，从而，贷款进一步相信线粒体结合HKII作为心脏功能，缺血-再灌注（IR）损伤和IPC的心脏保护的关键调节器的作用。
We have shown that partial dissociation of HKII from mitochondria in the intact heart using low dose (200 nM) TAT-HKII prevents the cardioprotective effects of ischemic preconditioning (IPC) whereas high-dose (10 μM) TAT-HKII administration results in rapid myocardial dysfunction, mitochondrial depolarization and disintegration. In this issue of Circulation Research, Pasdois et al argue that the deleterious effects of TAT-HKII administration on cardiac function are likely due to vasoconstriction and ensuing ischemia. To investigate whether altered vascular function and ensuing ischemia recapitulate the deleterious effects of TAT-HKII in intact myocardium. Using a variety of complementary techniques, including mitochondrial membrane potential (ΔΨm) imaging, high-resolution optical action potential (AP) mapping, analysis of lactate production, NADH epifluorescence, lactate dehydrogenase (LDH) release, and electron microscopy, we provide direct evidence that refutes the notion that acute myocardial dysfunction by high-dose TAT-HKII peptide administration is a consequence of impaired vascular function. Moreover, we demonstrate that low-dose TAT-HKII treatment, which abrogates the protective effects of IPC, is not associated with ischemia or ischemic-injury. Our findings challenge the notion that the effects of TAT-HKII are attributable to impaired vascular function and ensuing ischemia; thereby, lending further credence to the role of mitochondria bound HKII as a critical regulator of cardiac function, ischemia-reperfusion (IR) injury, and cardioprotection by IPC.