E2/ER β inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+-calcineurin signaling

• Published in: PloS one 2017-09, Vol.12 (9), p.e0184153-e0184153
• Main Authors: Tsai, Cheng-Yen, Kuo, Wei-Wen, Shibu, Marthandam Asokan, Lin, Yueh-Min, Liu, Chien-Nam, Chen, Yi-Hui, Day, Cecilia-Hsuan, Shen, Chia-Yao, Viswanadha, Vijaya Padma, Huang, Chih-Yang
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Aging; Aging (artificial); Animals; Apoptosis; Biology and Life Sciences; Ca2+/calmodulin-dependent protein kinase II; Calcineurin; Calcineurin - metabolism; Calcineurin Inhibitors - pharmacology; Calcium; Calcium (reticular); Calcium - metabolism; Calcium influx; Calcium signalling; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cardiac muscle; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomyocytes; Cardiovascular disease; Cell culture; Cell Nucleus - metabolism; Cycles; Enlargement; Estradiol - metabolism; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogens; Eutrophication; Female; Heart; Heart diseases; Heart failure; Hypertrophy; Isoproterenol - adverse effects; Kinases; Medicine and Health Sciences; Menstruation; Mortality; Myocytes, Cardiac - metabolism; Neurons - metabolism; NFATC Transcription Factors - metabolism; Penicillin; Phosphatase; Phosphorylation; Protein transport; Proteins; Rats; Receptors; Research and Analysis Methods; Rodents; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Sex hormones; Signal Transduction; Translocation; Up-Regulation - drug effects; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0184153

Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17β-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERβ against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac-hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast. However, overexpression of ERβ and/or administration of E2 inhibited ISO-induced hypertrophy in H9c2 cells. In addition, E2/ERβ also inhibited ISO-induced NFATc3 translocation, and reduced the protein level of downstream marker, BNP. Furthermore, by testing with the calcineurin inhibitor (CsA), it was confirmed that calcineurin acted as a key mediator for the anti-hypertrophic effect of E2/ERβ. In cells treated with calcium blocker (BATPA), the inhibitory effect of E2/ERβ on ISO-induced Ca2+ influx and hypertrophic effects were totally blocked suggesting that E2/ERβ inhibited calcineurin activity to activate I-1 protein and suppress PP1, then induce PLB protein phosphorylation and activation, resulting in Ca2+ reuptake into sarcoplasmic reticulum through SR Ca2+ cycling modification. In conclusion, E2/ERβ suppresses the Ca2+ influx and calcineurin activity induced by ISO to enhance the PLB protein activity and SR Ca2+ cycling.