title: Expression of Bcl2l1, Clcf1, IL-28ra and Pias1 in the mouse heart after single and repeated administration of chlorpromazine.
abstract: Several chlorpromazine (CPZ)-related deaths have been suspected in forensic autopsies but these are difficult to identify precisely because only low concentrations of CPZ can usually be detected. Patients on CPZ therapy exhibit various cardiovascular diseases, such as arrhythmia and cardiomyopathy. As our previous study revealed that CPZ administration affects the expression of immediate early genes that are induced before any other genes, we expected that CPZ probably affects the heart and, in particular, the gene expression in heart. CPZ changes tumor necrosis factor (TNF) production. After stimulation of TNF, the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway is activated via TNF receptor (TNF-R), and the pathway participates in the regulation of cellular responses such as apoptosis [1]. We used semi-arrays to determine the JAK-STAT signaling pathway in a mouse cardiomyocyte cell line, HL-1, and real-time quantitative-PCR to determine whether the semi-array data applied in vivo in mouse heart after single and once-daily repeated (1-4weeks) low-dose (0.75mg/kg) or high-dose (7.5mg/kg) CPZ treatment. We found that expression of B cell lymphoma 2 like 1 (Bcl2l1), Cardiotrophin-like cytokine factor 1 (Clcf1), Interleukin-28 receptor alpha (IL-28ra) and Protein inhibitor of activated STAT-1 (Pias1) were significantly changed in vivo. All these genes are associated with apoptosis. The expression level of Bcl2l1 was elevated after a single high-dose CPZ treatment and after 1week of repeated high doses, but returned to baseline from week 2 to week 4. Clcf1 and IL-28ra expression increased from week 2 or 3 after low-dose CPZ treatment. Pias1 also increased from week 2 after low-dose CPZ treatment. Our results indicate that different doses of CPZ can induce distinct patterns of gene expression for preventing the apoptotic progression in mouse cardiomyocytes, suggesting that CPZ can affect cardiomyocytes via the JAK-STAT signaling pathway and that this might lead to cardiomyopathy. In addition, our data may help to clarify the pathophysiology of cardiomyopathy induced by CPZ and to diagnose cardiac sudden death following CPZ treatment.
authors.affiliation: Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, Japan.
authors.forename: Chung-Ting
authors.initials: CT
authors.lastname: Tsai
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ikematsu
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sakai
authors.forename: Aya
authors.initials: A
authors.lastname: Matsuo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakasono
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D002746:Chlorpromazine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D050828:Protein Inhibitors of Activated STAT / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D014150:Antipsychotic Agents; D002746:Chlorpromazine; D016207:Cytokines; D050828:Protein Inhibitors of Activated STAT; D018121:Receptors, Cytokine; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C494211:Pias1 protein, mouse; C121169:cardiotrophin-like cytokine; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda; C471046:interleukin 28alpha receptor