Chia-Hui Chen1, Shr-Jeng Jim Leu2, Chiao-Po Hsu3, Ching-Chian Pan4, Song-Kun Shyue5, Tzong-Shyuan Lee6. 1. Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan. 2. Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan. 3. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 4. Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 5. Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: skshyue@ibms.sinica.edu.tw. 6. Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: ntutslee@ntu.edu.tw.
Abstract
BACKGROUND: Clinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored. METHODS: In this study, we used apolipoprotein E-deficient (apoe-/-) hyperlipidemic mice and apoe-/-cd36-/- mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells. RESULTS: In vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe-/- mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages. CONCLUSION: Collectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.
BACKGROUND: Clinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored. METHODS: In this study, we used apolipoprotein E-deficient (apoe-/-) hyperlipidemic mice and apoe-/-cd36-/- mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells. RESULTS: In vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe-/- mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages. CONCLUSION: Collectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.
Authors: Sara Guillen-Aguinaga; Antonio Brugos-Larumbe; Laura Guillen-Aguinaga; Felipe Ortuño; Francisco Guillen-Grima; Luis Forga; Ines Aguinaga-Ontoso Journal: J Cardiovasc Dev Dis Date: 2022-01-13