Department of Cardiology, The Third Hospital of Nanchang, Nanchang, Jiangxi 330009, China.
Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Pharmacol Res. 2014 Apr;82:40-50. doi: 10.1016/j.phrs.2014.03.010. Epub 2014 Apr 3.
Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential α,β-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca2+ decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca2+ property including depressed PS, ±dL/dt, ΔFFI and SERCA activity, as well as prolonged TR90 and intracellular Ca2+ decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1α and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism.
最近的证据表明，吸烟与心脏病患病率的增加有关。鉴于吸烟通过刺激辣椒素敏感的瞬时受体电位阳离子通道 TRPV1 引发促炎反应，本研究旨在评估香烟烟雾中的一种必需的α，β-不饱和醛丙烯醛对心肌功能的影响及其潜在机制，重点关注 TRPV1 和线粒体。评估了包括峰值缩短（PS）、缩短/延长的最大速度（±dL/dt）、PS 时间（TPS）、90%复长时间（TR90）、荧光强度（FFI）、细胞内 Ca2+ 衰减和 SERCA 活性在内的心肌细胞机械和细胞内 Ca2+ 特性。使用 Western blot 分析评估细胞凋亡和 TRPV1。使用细胞内荧光探针 5-（6）-氯甲基-2'，7'-二氯二氢荧光素二乙酸酯和 8-羟基-2'-脱氧鸟苷（8-OHdG）分别测量活性氧物种（ROS）和 DNA 损伤的产生。我们的数据显示，丙烯醛中断了心肌细胞的收缩和细胞内 Ca2+ 特性，包括 PS、±dL/dt、ΔFFI 和 SERCA 活性降低，以及 TR90 和细胞内 Ca2+ 衰减延长。丙烯醛暴露增加了 TRPV1 和 NADPH 氧化酶水平，促进了细胞凋亡、线粒体损伤（降低了乌头酸酶活性、PGC-1α 和 UCP-2）以及 ROS 和 8-OHdG 的产生。有趣的是，ROS 清除剂谷胱甘肽和 TRPV1 抑制剂辣椒素可消除丙烯醛引起的心脏缺陷。辣椒素（而非谷胱甘肽）消除了丙烯醛引起的线粒体损伤。辣椒素、谷胱甘肽和 NADPH 抑制剂阿朴肉桂醇可消除丙烯醛诱导的 ROS 积累。我们的数据表明，丙烯醛会损害心肌细胞的机械功能，可能是通过 TRPV1 和线粒体依赖的氧化应激机制。
