TRPA1 channel contributes to myocardial ischemia-reperfusion injury
TRPA1 channel contributes to myocardial ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.00106.2018
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发表时间：
2019-04-01
影响因子：
4.8
通讯作者：
Bhatnagar, Aruni
中科院分区：
文献类型：
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作者：
Conklin, Daniel J.;Guo, Yiru;Bhatnagar, Aruni
心肌缺血再灌注(I/R)导致自由基的产生、脂质过氧化产物不饱和醛的积聚、变异性心绞痛(Pain)和脑梗塞。瞬时受体潜在锚蛋白1(TRPA1)介导疼痛信号，并被不饱和醛激活，包括丙烯醛和4-羟基壬烯醛。TRPA1(一种钙离子通透通道)在I/R所致心肌损伤中的作用尚不清楚。我们验证了心脏TRPA1赋予心肌细胞对醛蓄积的敏感性并促进I/R损伤的假设。尽管TRPA1基因缺失小鼠的基础心血管功能与野生型(WT)小鼠相似，但TRPA1基因缺失小鼠的心肌梗死面积显著小于WT小鼠(34.1+/-9.3比14.3+/-9.9%的危险区，n=8和7，P<；(0.05)，尽管在原位心肌I/R(缺血30min，再灌注24小时)后，WT和TRPA1基因缺失小鼠的危险区域相似(分别为40.3+/-8.4%和42.2+/-11.3%)。TRPA1免疫荧光阳性存在于小鼠和人的心脏中，并与连接蛋白43共同定位于分离的小鼠心肌细胞的间盘。心肌细胞TRPA1经定量RT-PCR、DNA测序、Western印迹分析和电生理鉴定。在丙烯醛暴露的心肌细胞中，TRPA1在心肌细胞毒性中发挥作用。丙烯醛是一种I/R相关毒素，可诱导钙离子积聚和过度收缩，其作用可被TRPA1拮抗剂HC-030031显著减弱。HC-030031的保护作用与Na+/Ca~(2+)交换抑制剂SN-6的保护作用相当，进一步支持了钙超载在丙烯醛诱导的心肌细胞毒性中的作用。这些数据表明，心脏TRPA1的激活可能参与了心肌I/R损伤，因此，TRPA1可能成为减轻心肌I/R损伤的新的治疗靶点。新发现的值得注意的瞬时受体潜在蛋白Ankyrin 1(TRPA1)的激活介导了血流量增加、水肿和痛觉感受，但其在心肌缺血再灌注(I/R)损伤中的作用尚不清楚。基因消融TRPA1可显著减少小鼠心肌I/R后的心肌梗死。心肌细胞中的功能性TRPA1在插入盘中丰富，并参与了丙烯醛引起的钙超载和过度收缩。这些数据表明，TRPA1的I/R激活加重了心肌梗死；TRPA1可能是减轻I/R损伤的潜在靶点。
Myocardial ischemia-reperfusion (I/R) results in the generation of free radicals, accumulation of lipid peroxidation-derived unsaturated aldehydes, variable angina (pain), and infarction. The transient receptor potential ankyrin 1 (TRPA1) mediates pain signaling and is activated by unsaturated aldehydes, including acrolein and 4-hydroxynonenal. The contribution of TRPA1 (a Ca2+-permeable channel) to I/R-induced myocardial injury is unknown. We tested the hypothesis that cardiac TRPA1 confers myocyte sensitivity to aldehyde accumulation and promotes I/R injury. Although basal cardiovascular function in TRPA1-null mice was similar to that in wild-type (WT) mice, infarct size was significantly smaller in TRPA1-null mice than in WT mice (34.1 +/- 9.3 vs. 14.3 +/- 9.9% of the risk region, n = 8 and 7, respectively, P < 0.05), despite a similar I/R-induced area at risk (40.3 +/- 8.4% and 42.2 +/- 11.3% for WT and TRPA1-null mice, respectively) after myocardial I/R (30 min of ischemia followed by 24 h of reperfusion) in situ. Positive TRPA1 immunofluorescence was present in murine and human hearts and was colocalized with connexin43 at intercalated disks in isolated murine cardiomyocytes. Cardiomyocyte TRPA1 was confirmed by quantitative RT-PCR, DNA sequencing, Western blot analysis, and electrophysiology. A role of TRPA1 in cardiomyocyte toxicity was demonstrated in isolated cardiomyocytes exposed to acrolein, an I/R-associated toxin that induces Ca2+ accumulation and hypercontraction, effects significantly blunted by HC-030031, a TRPA1 antagonist. Protection induced by HC-030031 was quantitatively equivalent to that induced by SN-6, a Na+/Ca2+ exchange inhibitor, further supporting a role of Ca2+ overload in acrolein-induced cardiomyocyte toxicity. These data indicate that cardiac TRPA1 activation likely contributes to I/R injury and, thus, that TRPA1 may be a novel therapeutic target for decreasing myocardial I/R injury.NEW & NOTEWORTHY Transient receptor potential ankyrin 1 (TRPA1) activation mediates increased blood flow, edema, and pain reception, yet its role in myocardial ischemia-reperfusion (I/R) injury is unknown. Genetic ablation of TRPA1 significantly decreased myocardial infarction after I/R in mice. Functional TRPA1 in cardiomyocytes was enriched in intercalated disks and contributed to acrolein-induced Ca2+ overload and hypercontraction. These data indicate that I/R activation of TRPA1 worsens myocardial infarction; TRPA1 may be a potential target to mitigate I/R injury.