第二代抗精神病药通过CB1R导致心肌细胞焦亡的作用机制及临床意义

第二代抗精神病药是目前临床治疗多种精神障碍的一线用药，但其心肌毒性限制了临床应用。我们前期发现氯氮平、喹硫平等第二代抗精神病药促进了心肌1型大麻素受体（CB1R）的表达及内化，从而引起心肌肥厚、纤维沉积等心肌损伤改变。近期又发现，在第二代抗精神病药相关心源性猝死案例中，心肌细胞焦亡通路显著激活。据此提出科学假设：第二代抗精神病药通过诱导CB1R高表达，导致了心肌细胞焦亡及损伤。本项目将①首先在抗精神病药相关人体心肌样本中确证CB1R蛋白水平、细胞焦亡及心肌损伤程度之间的相关性；②从体内、外水平阐明心肌细胞焦亡在第二代抗精神病药诱导心肌损伤中的作用；③观察心肌CB1R特异性敲除及药物干扰后第二代抗精神病药诱导心肌细胞焦亡及损伤的改变，并解析CB1R调控心肌细胞焦亡的具体机制。本项目将阐明第二代抗精神病药心肌损伤机制，为该类药物心肌损伤的防治提供新靶点。

Second-generation antipsychotics are first-line drugs used for treating various mental disorders in clinic, but their cardiotoxicity restricted their clinical application. We previously found that second-generation antipsychotics clozapine and quetiapine upregulated cannabinoid receptor 1 (CB1R) and promoted its internalization and therefore led to myocardial injury such as cardiac hypertrophy and fibrosis accumulation. Recently we have further found that in the antipsychotics-related sudden cardiac deaths samples, cardiomyocyte pyroptosis was significantly activated. Therefore, we hypothesized that second-generation antipsychotics induced pyroptosis and myocardial injury through upregulating CB1R expression. This project will ①initially validate the association of CB1R and pyroptosis molecules expression with the severity of myocardial injury in antipsychotics-associated human heart specimens; ②investigate the role of pyroptosis in antipsychotics-induced myocardial injury from in vivo and in vitro levels; ③observe the changes of antipsychotics-induced pyroptosis and myocardial injury after cardiomyocyte-specific CB1R deletion by gene editing or antagonists, and then probe the detailed mechanisms how CB1R regulates pyroptosis. This project will uncover the mechanisms of second-generation antipsychotics-induced myocardial injury, and provide therapeutic targets for the prevention and treatment of these drugs-related myocardial injury.