Nicotine induces cardiac toxicity through blocking mitophagic clearance in young adult rat
Nicotine induces cardiac toxicity through blocking mitophagic clearance in young adult rat
复制标题
尼古丁通过阻断年轻成年大鼠线粒体自噬清除诱导心脏毒性
DOI：
10.1016/j.lfs.2020.118084
复制
发表时间：
2020-09-15
期刊：
影响因子：
6.1
通讯作者：
Wang, Yajing
中科院分区：
文献类型：
--
作者：
Jia, Guizhi;Meng, Zhijun;Wang, Yajing
自美国爆发与蒸发相关的死亡事件被报告为公共健康危机以来，由于电子烟等烟草香烟替代品的使用，尼古丁对心血管的安全性如今受到越来越多的关注。然而，尼古丁是否以及如何对心脏产生有害影响仍存在很大争议，尤其是在年轻人中知之甚少。我们报道，与假手术相比，慢性尼古丁暴露，电子烟的主要成分，导致直接抑制心肌细胞活性，增加心脏纤维化，并显著抑制心功能。基因芯片结合生物信息学分析证实，心肌细胞凋亡和有丝分裂是尼古丁致心脏损害的关键信号。从机制上讲，尼古丁暴露显著增加Caspase3和Caspase9的裂解，提示参与了内源性的细胞凋亡途径(线粒体细胞死亡途径)。同时，尼古丁诱导的ROS爆发促进了线粒体的碱化，进而阻止了有丝分裂的降解，从而阻断了有丝分裂的通量，促进了线粒体细胞死亡的级联反应。综上所述，这些发现表明尼古丁通过ROS诱导的线粒体通透性阻断而产生心脏毒性，并首次证明尼古丁与年轻成年大鼠的心脏毒性之间存在因果联系，这可能表明尼古丁导致年轻成年大鼠的心肌细胞损伤，从而导致心脏毒性。
Since an outbreak of vaping-related deaths in the US has been reported as a public health crisis, the cardiovascular safety of nicotine nowadays receives increasing attention due to use of tobacco cigarette alternatives, such as electronic cigarettes. However, whether and how nicotine contributes to cardiac detrimental effects are in great controversy, especially less understood in young adult population. We report that chronic nicotine exposure, a major component of Electronic cigarettes, resulted in directly inhibited cardiomyocytes viability, increased cardiac fibrosis, and markedly suppressed cardiac function compared with sham. Gene array combined with bioinformatics analysis identified cardiac apoptosis and mitophagy were the key signals responsible for nicotine induced cardiac detrimental effect. Mechanistically, nicotine exposure markedly increased cleaved Caspase 3 and cleaved Caspase 9 indicating the involvement of intrinsic apoptotic pathway (mitochondrial cell death pathway). Meanwhile, nicotine-induced ROS outbreak promoted lysomal alkalization, furthermore blocked mitophagic degradation, thereby disrupted mitophagic flux promoted mitochondrial cell death cascade. Taken together, these findings indicate that nicotine confers cardiotoxicity via ROS-induced mitophagic flux blockage and provide the first demonstration of a causative link between nicotine and cardiac toxicity in young adult rat which may suggest nicotine induces cardiomyocytes impairment leading to cardiotoxicity in young adult population.