title: Genome-wide analysis of tunicamycin-induced endoplasmic reticulum stress response and the protective effect of endoplasmic reticulum inhibitors in neonatal rat cardiomyocytes.
abstract: Tunicamycin (TM) is an inducer of endoplasmic reticulum (ER) stress. However, which genes related to ER stress was induced in cardiomyocytes on a genome-wide scale remains poorly understood. Salubrinal and its derivatives are ER stress inhibitors. However, the cellular protection mechanisms remain unresolved. Neonatal rat cardiomyocytes were cultured from ventricles of one-day-old Wistar rats. Cells were exposed to salubrinal, its derivatives (PP1-12, PP1-24) or vehicle followed by TM treatment at different times. Total RNA was isolated from cells for RNA-sequencing analysis. The expressions of 189, 182, 556, 860, and 1314 genes were changed in cells exposed to TM for 1, 3, 6, 12, and 24 h. Five well-known UPR genes (Hspa5, Hsp90b1, Calr, Ddit3, and Atf4) were significantly increased in a time-dependent manner. Six not well-known genes (Hyou1, Herpud1, Manf, Creld2, Sdf2l1, and Slc3a2) were highlighted to be involved in ER stress. Compared with TM-only treated cells, the expressions of 36 genes upregulated by TM and 74 genes downregulated by TM were reversed by salubrinal. In comparison, 121 genes upregulated by TM and 92 genes downregulated by TM were reversed by PP1-12. Most genes altered by salubrinal are in the category of transcription (1 h) and cell cycle (24 h). Most genes altered by PP1-12 are in the category of response to ER stress (3 h) and cell cycle (24 h). Our findings help elucidate the mechanism for TM treatment and may be useful for future drug screens involved in ER stress.
authors.affiliation: Department of Geriatric Cardiology, The General Hospital of Chinese People's Liberation Army, NO. 28, Fuxing Road, Haidian District, Beijing, 100853, China.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, NO. 27, Taiping Road, Haidian District, Beijing, 100850, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Geriatric Cardiology, The General Hospital of Chinese People's Liberation Army, NO. 28, Fuxing Road, Haidian District, Beijing, 100853, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: He
authors.affiliation: Department of Geriatric Cardiology, The General Hospital of Chinese People's Liberation Army, NO. 28, Fuxing Road, Haidian District, Beijing, 100853, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Geriatric Cardiology, The General Hospital of Chinese People's Liberation Army, NO. 28, Fuxing Road, Haidian District, Beijing, 100853, China. lis@bmi.ac.cn.|Beijing Institute of Pharmacology and Toxicology, NO. 27, Taiping Road, Haidian District, Beijing, 100850, China. lis@bmi.ac.cn.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Geriatric Cardiology, The General Hospital of Chinese People's Liberation Army, NO. 28, Fuxing Road, Haidian District, Beijing, 100853, China. hekl301@aliyun.com.
authors.forename: Kun-Lun
authors.initials: KL
authors.lastname: He
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017423:Sequence Analysis, RNA / Q000379:methods; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology*
chemical_list: D002934:Cinnamates; C496827:salubrinal; D014415:Tunicamycin; D013890:Thiourea
keywords: Cardiomyopathy; Endoplasmic reticulum stress; RNA-seq; UPR