title: Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation.
abstract: IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy.
authors.affiliation: * Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Yueh-Shan
authors.initials: YS
authors.lastname: Weng
authors.affiliation: ¶ Institute of Biomedical Nutrition, Hungkuang University, Taichung, Taiwan.
authors.forename: Hsueh-Fang
authors.initials: HF
authors.lastname: Wang
authors.affiliation: ∥ Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Pai
authors.affiliation: ** Division of Cardiology, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: Gwo-Ping
authors.initials: GP
authors.lastname: Jong
authors.affiliation: † Graduate Institute of Aging Medicine, China Medical University, Taichung, Taiwan.|** Division of Cardiology, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Lai
authors.affiliation: †† Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy & Science, Tainan County, Taiwan.
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Chung
authors.affiliation: ‡‡ School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Dennis Jine-Yuan
authors.initials: DJ
authors.lastname: Hsieh
authors.affiliation: §§ Department of Nursing, Mei Ho University, Pingguang Road, Pingtung, Taiwan.
authors.forename: Cecilia
authors.initials: C
authors.lastname: HsuanDay
authors.affiliation: ‡ Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: * Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan.|§ Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|¶¶ Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002316:Cardiotonic Agents; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D000077267:Fulvestrant; D006984:Hypertrophy / Q000235:genetics / Q000517:prevention & control; D007335:Insulin-Like Growth Factor II / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D008517:Phytotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism / Q000502:physiology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D045784:Abietanes; D002316:Cardiotonic Agents; D050778:NFATC Transcription Factors; D017527:Receptor, IGF Type 2; D011960:Receptors, Estrogen; C445503:transcription factor NF-AT c3; C021751:tanshinone; D000077267:Fulvestrant; D004958:Estradiol; D007335:Insulin-Like Growth Factor II; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin
keywords: Calcineurin/NFAT3; Cardiac Hypertrophy; IGF-II Receptor; Selective Estrogen Receptor Modulator; Tanshinone IIA; p-Akt