Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore.
Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore.
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DOI：
10.1093/cvr/cvv226
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发表时间：
2015-12-01
影响因子：
10.8
通讯作者：
Yellon DM
中科院分区：
文献类型：
--
作者：
Davidson SM;Foote K;Kunuthur S;Gosain R;Tan N;Tyser R;Zhao YJ;Graeff R;Ganesan A;Duchen MR;Patel S;Yellon DM
在心脏，一段时间的缺血和再灌流会引起强烈的细胞内钙振荡，从而导致致命的细胞损伤。这些信号代表了有吸引力的心脏保护靶点，但其发生的潜在机制尚不清楚。在这里，我们研究了第二信使烟酸腺嘌呤二核苷酸磷酸(NAADP)的作用，它在几种细胞类型中已知诱导钙振荡，这种振荡始于酸性存储，如溶酶体，可能通过两孔通道(TPC，TPC1和2)。NAADP拮抗剂Ned-K是在已有支架的基础上经过合理设计开发出来的。NED-K抑制钙离子振荡，显著保护体外培养的心肌细胞免受缺血和复氧后的细胞死亡，阻止线粒体通透性转换孔的开放。Ned-K可显著缩小小鼠在体脑梗塞面积。缺乏内切溶酶体TPC1的转基因小鼠也免受损伤。NAADP信号在再灌注诱导的细胞死亡中起重要作用，是保护再灌注损伤的有效途径。
In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca2+ oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but the underlying mechanisms of genesis are ill-defined. Here, we investigated the role of the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several cell types to induce Ca2+ oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2). An NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca2+ oscillations and dramatically protected cardiomyocytes from cell death in vitro after ischaemia and reoxygenation, preventing opening of the mitochondrial permeability transition pore. Ned-K profoundly decreased infarct size in mice in vivo. Transgenic mice lacking the endo-lysosomal TPC1 were also protected from injury. NAADP signalling plays a major role in reperfusion-induced cell death and represents a potent pathway for protection against reperfusion injury.