HNO Protects the Myocardium against Reperfusion Injury, Inhibiting the mPTP Opening via PKCε Activation.
HNO Protects the Myocardium against Reperfusion Injury, Inhibiting the mPTP Opening via PKCε Activation.
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DOI：
10.3390/antiox11020382
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发表时间：
2022-02-14
期刊：
影响因子：
--
通讯作者：
Paolocci N
中科院分区：
文献类型：
--
作者：
Mancardi D;Pagliaro P;Ridnour LA;Tocchetti CG;Miranda K;Juhaszova M;Sollott SJ;Wink DA;Paolocci N
氮氧供体(HNO)是一氧化氮(NO)的一个电子还原产物，在限制缺血再灌注(I/R)损伤的同时，对心肌的收缩/松弛有积极的调节作用。HNO抗缺血作用的机制尚不清楚。采用大鼠离体心全脑缺血30min/再灌流1或2小时的模型，与NO类似，我们测试了HNO的保护作用是否需要PKCε转位到线粒体和KATP通道激活。为此，我们比较了缺血预适应(IPC；3个I/R周期)和NO最终给予的益处。供体，二乙胺/NO，DEA/NO，以及两个化学上不相关的HNO供体：Angeli盐(AS，原型供体)和异丙胺/NO(IPA/NO，一种新的HNO释放剂)。所有供体在I/R损伤前给予19min。在对照I/R心脏(再灌流1h)，四唑盐染色测得的梗塞面积(IS)为危险面积的66±5.5%。AS和IPA/NO在降低IS方面与IPC一样有效[分别为30.7±2.2(AS)、31±2.9(IPA/NO)和31±0.8(IPC)]，而DEA/NO降低IS的效果显著低于IPC(36.2±2.6%，p<0.001)。IPA/NO在再灌流120min后仍有保护作用，与PKCε抑制剂(PKCV1-2500 nM)联合应用可阻止IPA/NO的保护作用(IS=30±0.5vs.61±1.8%，p<；0.01)。与供体无关，HNO的抗缺血作用对KATP通道阻断剂5-羟基癸酸酯(5HD，100μM)不敏感，相反，后者取消了DEA/NO的保护作用。最后，两个HNO供体都显著提高了线粒体通透性转换孔的ROS阈值，高于对照水平(≅35-40%)，这一作用再次对5HD不敏感。我们的研究表明，HNO供体抑制MPTP的开放，从而限制再灌注时心肌细胞的丢失，这一有益的效果需要蛋白激酶Cε转位到线粒体，而不是线粒体K+通道的激活。
Donors of nitroxyl (HNO), the one electron-reduction product of nitric oxide (NO.), positively modulate cardiac contractility/relaxation while limiting ischemia-reperfusion (I/R) injury. The mechanisms underpinning HNO anti-ischemic effects remain poorly understood. Using isolated perfused rat hearts subjected to 30 min global ischemia/1 or 2 h reperfusion, here we tested whether, in analogy to NO., HNO protection requires PKCε translocation to mitochondria and KATP channels activation. To this end, we compared the benefits afforded by ischemic preconditioning (IPC; 3 cycles of I/R) with those eventually granted by the NO. donor, diethylamine/NO, DEA/NO, and two chemically unrelated HNO donors: Angeli’s salt (AS, a prototypic donor) and isopropylamine/NO (IPA/NO, a new HNO releaser). All donors were given for 19 min before I/R injury. In control I/R hearts (1 h reperfusion), infarct size (IS) measured via tetrazolium salt staining was 66 ± 5.5% of the area at risk. Both AS and IPA/NO were as effective as IPC in reducing IS [30.7 ± 2.2 (AS), 31 ± 2.9 (IPA/NO), and 31 ± 0.8 (IPC), respectively)], whereas DEA/NO was significantly less so (36.2 ± 2.6%, p < 0.001 vs. AS, IPA/NO, or IPC). IPA/NO protection was still present after 120 min of reperfusion, and the co-infusion with the PKCε inhibitor (PKCV1-2500 nM) prevented it (IS = 30 ± 0.5 vs. 61 ± 1.8% with IPA/NO alone, p < 0.01). Irrespective of the donor, HNO anti-ischemic effects were insensitive to the KATP channel inhibitor, 5-OH decanoate (5HD, 100 μM), that, in contrast, abrogated DEA/NO protection. Finally, both HNO donors markedly enhanced the mitochondrial permeability transition pore (mPTP) ROS threshold over control levels (≅35–40%), an action again insensitive to 5HD. Our study shows that HNO donors inhibit mPTP opening, thus limiting myocyte loss at reperfusion, a beneficial effect that requires PKCε translocation to the mitochondria but not mitochondrial K+ channels activation.
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DOI：
10.1111/j.1749-6632.2002.tb04053.x
发表时间：
2002-01-01
期刊：
NITRIC OXIDE: NOVEL ACTIONS, DELETERIOUS EFFECTS AND CLINICAL POTENTIAL
影响因子：
--
作者：
Dawn, B;Bolli, R
通讯作者：
Bolli, R
影响因子：
5
作者：
Paolocci, N;Biondi, R;Zweier, JL
通讯作者：
Zweier, JL
影响因子：
2.9
作者：
Cowart, Douglas;Venuti, Robert P.;Foo, Shi Yin
通讯作者：
Foo, Shi Yin
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
DOI：
10.1073/pnas.96.25.14617
发表时间：
1999-12-07
影响因子：
11.1
作者：
Ma, XL;Cao, F;Feelisch, M
通讯作者：
Feelisch, M