17β-Estradiol and/or estrogen receptor alpha signaling blocks protein phosphatase 1 mediated ISO induced cardiac hypertrophy

• Published in: PloS one Vol. 13; no. 5; p. e0196569
• Main Authors: Fang, Hsin-Yuan, Hung, Meng-Yu, Lin, Yueh-Min, Pandey, Sudhir, Chang, Chia-Chien, Lin, Kuan-Ho, Shen, Chia-Yao, Viswanadha, Vijaya Padma, Kuo, Wei-Wen, Huang, Chih-Yang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2018; Public Library of Science (PLoS)
• Subjects: 17β-Estradiol; Activation; Adenosine triphosphatase; Animals; Apoptosis; Biology and Life Sciences; Ca2+-transporting ATPase; Calcium; Calcium (reticular); Calcium - metabolism; Calcium ions; Cardiac function; Cardiac muscle; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomegaly - prevention & control; Cardiomyocytes; Cell Enlargement - drug effects; Cell Line; Cell size; Estradiol - metabolism; Estradiol - pharmacology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Gene expression; Heart; Heart failure; Hormone replacement therapy; Hospitals; Hypertrophy; Inhibitors; Isoproterenol; Isoproterenol - toxicity; Medical research; Medicine and Health Sciences; Melatonin; Models, Cardiovascular; Molecular modelling; Musculoskeletal system; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphatase; Phospholamban; Phosphoprotein phosphatase; Phosphorylation; Protein phosphatase; Protein Phosphatase 1 - metabolism; Proteins; Rats; Research and Analysis Methods; Rodents; Sarcoplasmic reticulum; Serine; Sex hormones; Signal transduction; Signal Transduction - drug effects; Signaling; Stem cells; Thoracic surgery; Threonine; United States > US; China; Missouri; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0196569

Earlier studies have shown that estrogen possess protective function against the development of pathological cardiac hypertrophy. However, the molecular mechanisms of estrogens (E2) protective effect are poorly understood. Additionally, abnormal activation of β-adrenergic signaling have been implicated in the development of pathological cardiac remodeling. However, the role of serine/threonine protein phosphatase 1 (PP1) in pathological cardiac remodeling under the influence of β-adrenergic signaling have been sparsely investigated. In this study, we assessed the downstream effects of abnormal activation of PP1 upon isoproterenol (ISO) induced pathological cardiac changes. We found that pre-treatment of 17β-estradiol (E2), tet-on estrogen receptor-α, or both significantly inhibited ISO-induced increase in cell size, hypertrophy marker gene expression and cytosolic calcium accumulation in H9c2 cells. Additionally, treatment with estrogen receptor inhibitor (ICI) reversed those effects, implicating role of E2 in inhibiting pathological cardiac remodeling. However, specific inhibition of ERα using melatonin, reduced ISO-induced PP1c expression and enhanced the level of ser-16 phosphorylated phospholamban (PLB), responsible for regulation of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Furthermore, hypertrophic effect caused by overexpression of PP1cα was reduced by treatment with specific inhibitor of ERα. Collectively, we found that estrogen and estrogen receptor-α have protective effect against pathological cardiac changes by suppressing PP1 expression and its downstream signaling pathway, which further needs to be elucidated.