Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
J Pharmacol Exp Ther. 2012 Oct;343(1):97-105. doi: 10.1124/jpet.112.196626. Epub 2012 Jul 3.
During myocardial ischemia/reperfusion, lipid peroxidation leads to the formation of toxic aldehydes that contribute to ischemic dysfunction. Mitochondrial aldehyde dehydrogenase type 2 (ALDH2) alleviates ischemic heart damage and reperfusion arrhythmias via aldehyde detoxification. Because excessive norepinephrine release in the heart is a pivotal arrhythmogenic mechanism, we hypothesized that neuronal ALDH2 activation might diminish ischemic norepinephrine release. Incubation of cardiac sympathetic nerve endings with acetaldehyde, at concentrations achieved in myocardial ischemia, caused a concentration-dependent increase in norepinephrine release. A major increase in norepinephrine release also occurred when sympathetic nerve endings were incubated in hypoxic conditions. ALDH2 activation substantially reduced acetaldehyde- and hypoxia-induced norepinephrine release, an action prevented by inhibition of ALDH2 or protein kinase Cε (PKCε). Selective activation of G(i/o)-coupled adenosine A(1), A(3), or histamine H(3) receptors markedly inhibited both acetaldehyde- and hypoxia-induced norepinephrine release. These effects were also abolished by PKCε and/or ALDH2 inhibition. Moreover, A(1)-, A(3)-, or H(3)-receptor activation increased ALDH2 activity in a sympathetic neuron model (differentiated PC12 cells stably transfected with H(3) receptors). This action was prevented by the inhibition of PKCε and ALDH2. Our findings suggest the existence in sympathetic neurons of a protective pathway initiated by A(1)-, A(3)-, and H(3)-receptor activation by adenosine and histamine released in close proximity of these terminals. This pathway comprises the sequential activation of PKCε and ALDH2, culminating in aldehyde detoxification and inhibition of hypoxic norepinephrine release. Thus, pharmacological activation of PKCε and ALDH2 in cardiac sympathetic nerves may have significant protective effects by alleviating norepinephrine-induced life-threatening arrhythmias that characterize myocardial ischemia/reperfusion.
在心肌缺血/再灌注期间，脂质过氧化导致有毒醛的形成，这些醛有助于缺血性功能障碍。线粒体醛脱氢酶 2（ALDH2）通过醛解毒减轻缺血性心脏损伤和再灌注心律失常。因为心脏中过量的去甲肾上腺素释放是关键的心律失常机制，所以我们假设神经元 ALDH2 的激活可能会减少缺血性去甲肾上腺素的释放。在心肌缺血时达到的浓度下，将乙醛孵育在心脏交感神经末梢中，会导致去甲肾上腺素释放呈浓度依赖性增加。当在缺氧条件下孵育交感神经末梢时，去甲肾上腺素的释放也会大幅增加。ALDH2 的激活可显著减少乙醛和缺氧诱导的去甲肾上腺素释放，该作用可被 ALDH2 或蛋白激酶 Cε（PKCε）的抑制所阻止。选择性激活 G(i/o)-偶联的腺苷 A(1)、A(3)或组胺 H(3)受体，可显著抑制乙醛和缺氧诱导的去甲肾上腺素释放。这些作用也被 PKCε 和/或 ALDH2 的抑制所消除。此外，A(1)、A(3)或 H(3)受体的激活在稳定转染 H(3)受体的分化 PC12 细胞的交感神经元模型中增加了 ALDH2 活性。该作用被 PKCε 和 ALDH2 的抑制所阻止。我们的研究结果表明，在交感神经元中存在一种保护途径，该途径由在这些末梢附近释放的腺苷和组胺激活的 A(1)、A(3)和 H(3)受体引发。该途径包括 PKCε 和 ALDH2 的顺序激活，最终导致醛的解毒和缺氧去甲肾上腺素释放的抑制。因此，通过减轻心肌缺血/再灌注过程中表现出的危及生命的心律失常，在心脏交感神经中激活 PKCε 和 ALDH2 可能具有显著的保护作用。
