Chen Chia-Hui, Chen Wen-Hua, Hsu Chiao-Po, Lee Tzong-Shyuan
Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Biomed Pharmacother. 2025 Apr;185:117958. doi: 10.1016/j.biopha.2025.117958. Epub 2025 Mar 8.
Patients with schizophrenia receiving atypical antipsychotics have an increased risk of metabolic syndrome; however, the efficacy of statins in mitigating cardiovascular risks in these patients remains unclear. This study examined the effects of typical and atypical antipsychotics on the lipid-lowering efficacy of statins in schizophrenia patients and investigated the underlying mechanisms of simvastatin action in hepatocytes and endothelial cells (ECs). A retrospective analysis revealed that statins were less effective in lowering LDL levels in patients on atypical antipsychotics. In vitro, olanzapine attenuated the beneficial effects of simvastatin in hepatocytes and ECs. Mechanistically, olanzapine downregulated dimethylarginine dimethylaminohydrolase 1 (DDAH1) and/or DDAH2, leading to elevated asymmetric dimethylarginine (ADMA) levels in both cell types. In hepatocytes, olanzapine suppressed low-density lipoprotein receptor (LDLR) expression and reduced LDL binding by activating the NOX-ROS pathway via PPARγ-PCSK9- and LXRα-IDOL-dependent signaling. Inhibition of the NOX-ROS pathway restored LDLR expression, LDL binding, and the lipid-lowering effects of simvastatin. In ECs, olanzapine impaired simvastatin-induced nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation through NOX-ROS pathway activation. Blocking this pathway reversed eNOS inhibition, restoring the endothelial benefits of simvastatin. Collectively, atypical antipsychotics impair statin efficacy in schizophrenia patients by activating the ADMA-NOX-ROS pathway, which downregulates LDLR in hepatocytes and inhibits eNOS activity in ECs. These findings underscore the need for tailored cardiovascular risk management strategies and identify potential molecular targets to enhance statin effectiveness in patients on atypical antipsychotics.
接受非典型抗精神病药物治疗的精神分裂症患者患代谢综合征的风险增加；然而，他汀类药物在降低这些患者心血管风险方面的疗效仍不明确。本研究考察了典型和非典型抗精神病药物对精神分裂症患者他汀类药物降脂疗效的影响，并研究了辛伐他汀在肝细胞和内皮细胞（ECs）中的作用机制。一项回顾性分析显示，他汀类药物在降低使用非典型抗精神病药物患者的低密度脂蛋白（LDL）水平方面效果较差。在体外，奥氮平减弱了辛伐他汀在肝细胞和ECs中的有益作用。从机制上讲，奥氮平下调二甲基精氨酸二甲胺水解酶1（DDAH1）和/或DDAH2，导致两种细胞类型中不对称二甲基精氨酸（ADMA）水平升高。在肝细胞中，奥氮平通过PPARγ-PCSK9-和LXRα-IDOL依赖性信号通路激活NOX-ROS途径，抑制低密度脂蛋白受体（LDLR）表达并减少LDL结合。抑制NOX-ROS途径可恢复LDLR表达、LDL结合以及辛伐他汀的降脂作用。在ECs中，奥氮平通过激活NOX-ROS途径损害辛伐他汀诱导的一氧化氮（NO）生成和内皮型一氧化氮合酶（eNOS）磷酸化。阻断该途径可逆转eNOS抑制，恢复辛伐他汀的内皮保护作用。总体而言，非典型抗精神病药物通过激活ADMA-NOX-ROS途径损害精神分裂症患者的他汀类药物疗效，该途径下调肝细胞中的LDLR并抑制ECs中的eNOS活性。这些发现强调了制定针对性心血管风险管理策略的必要性，并确定了潜在的分子靶点，以提高非典型抗精神病药物治疗患者的他汀类药物疗效。
