TRPing up reperfusion: neutrophil TRPM2 channels exacerbate necrosis and contractile dysfunction in post-ischaemic myocardium.
TRPing up reperfusion: neutrophil TRPM2 channels exacerbate necrosis and contractile dysfunction in post-ischaemic myocardium.
复制标题
TRP 促进再灌注：中性粒细胞 TRPM2 通道会加剧缺血后心肌的坏死和收缩功能障碍。
DOI：
10.1093/cvr/cvs365
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发表时间：
2013
影响因子：
10.8
通讯作者：
Kalogeris,Theodore
中科院分区：
文献类型：
--
作者：
Korthuis,RonaldJ;Kalogeris,Theodore
Myocardial infarction, stroke, and other ischaemic disorders are leading causes of morbidity and mortality. As a consequence, intensive research efforts have been directed at determining the mechanisms underlying cell death and dysfunction induced by ischaemia. Although reperfusion is essential to rescue ischaemic tissues, re-establishing the blood supply is not without peril as it can provoke overproduction of reactive oxygen and nitrogen species (ROS, RNS), inflammation, and an excessive rise in intracellular calcium levels as common triggers for cell dysfunction and death in post-ischaemic tissues. Thus, oxidative/nitrosative stress, neutrophils, other immunocytes, and calcium overload are now recognized as key contributors to the reperfusion-induced component of total tissue injury sustained in organs subjected to ischaemia/reperfusion (I/R). 1 Although a number of calcium channels have been implicated in I/R, recent work has focused attention on the potential role of redoxsensitive transient receptor potential melastatin 2 (TRPM2) channels as novel mediators. 1–5 These channels consist of six transmembrane domains and intracellular N and C termini that form monovalent cation channels with selectivity for Ca2+ and to a lesser extent Mg2+. 2–5 TRPM2 channels are expressed by a variety of cells and together with TRPM6 and TRPM7 are unique among ion channels in that their C-terminus contains enzymatic domains that exhibit ADP ribose (ADPR) pyrophosphatase activity, providing this domain with a site for ADPR binding and activation of the channel. 2–5 With regard to mechanisms relevant to I/R, TRPM2 channels are also activated by direct oxidation of channel moieties by H2O2 or indirectly via activation of enzymatic pathways [poly (ADPR) polymerase (PARP), poly (ADPR) glycohydrolase, or the NAD/cADPR glycohydrolases CD38 and CD157] involved in the formation of ADPR. 2–5 On the basis of this information, it is tempting to speculate that the anti-inflammatory and infarct-sparing effects of PARP inhibition in cardiac I/R 6 may be related to attendant reductions in TRPM2 activation. This mechanism is also thought to mediate TRPM2 activation by tumour necrosis factor-a (TNF-a), an inflammatory mediator that plays a key role in the pathogenesis of I/R. 1, 7 Changes in intracellular Ca2+ levels also facilitate channel activation by ADPR, 2–5 which further supports a potential role for TRPM2 in the pathogenesis of I/R. Indeed, knockdown of TRPM2 expression or pharmacological inhibition of channel activity has been shown to reduce neural injury in experimental stroke. 8, 9 In this issue of Cardiovascular Research, Hiroi et al. 10 not only extend these observations to myocardial I/R injury, they further show that TRPM2 channels expressed on neutrophils play a key role in exacerbating post-ischaemic contractile function and the size of an evolving infarct, but do not contribute to the ischaemic component of total tissue injury in I/R (Figure 1). The latter observation is consistent with the effect of ischaemia to induce acidosis, which has been shown to inhibit TRPM2. 4 The most convincing evidence provided by Hiroi et al. 10 to support this novel role for neutrophil TRPM2 in myocardial reperfusion injury is derived from studies showing that:(i) myocardial infarct size and contractile dysfunction were reduced after I/R, but not ischaemia alone, in TRPM2 knockout mice (TRPM 2 J/J) compared with wild-type animals (WT);(ii) cardiac neutrophil infiltration was reduced after I/R in TRPM2J/J vs. WT mice;(iii) an increased intracellular Ca2+ concentration and increased endothelial cell adhesive interactions were noted for neutrophils obtained from …
