Estrogen receptor α supports cardiomyocytes indirectly through post-infarct cardiac c-kit+ cells

• Published in: Journal of molecular and cellular cardiology Vol. 47; no. 1; pp. 66 - 75
• Main Authors: Brinckmann, Marie, Kaschina, Elena, Altarche-Xifró, Wassim, Curato, Caterina, Timm, Melanie, Grzesiak, Aleksandra, Dong, Jun, Kappert, Kai, Kintscher, Ulrich, Unger, Thomas, Li, Jun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2009
• Subjects: Animals; Cardiac c-kit+ cell; Cardiomyocyte; Cardioprotection; Cardiovascular; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Coculture Techniques; Estradiol - pharmacology; Estrogen receptor; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - metabolism; Estrogen Receptor alpha - physiology; Flow Cytometry; Fluorescent Antibody Technique; Immunoblotting; Male; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Myocardial infarction; Myocardial Infarction - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Phenols; Polymerase Chain Reaction; Proto-Oncogene Proteins c-kit - metabolism; Pyrazoles - pharmacology; Rats; Rats, Wistar; Myocardial infarction; Estrogen receptor; Cardioprotection; Cardiac c-kit+ cell; Cardiomyocyte
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2009.03.014

Abstract Despite previous studies demonstrating a cardioprotective role of estradiol via its estrogen receptor (ER)α, the underlying mechanisms remain unclear. Here we aimed to define ERα-involved mechanisms against cardiac injury. Seven days after myocardial infarction in male rats, cardiac ERα was upregulated in post-infarct cardiac c-kit+ cells accumulating in periinfarct myocardium as shown by Western blotting and immunofluorescence staining. Further, we isolated post-infarct cardiac c-kit+ cell population by modified magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS), and confirmed predominant ERα expression in this post-infarct cardiac c-kit+ cell population by real-time PCR. These post-infarct cardiac c-kit+ cells, characterized by upregulated transcription factors implicated in cardiogenic differentiation (GATA-4, Notch-2) and genes required for self-renewal (Tbx3, Akt), maintained a stable phenotype in vitro for more than 3 months. ERα stimulation supported proliferation but prevented differentiation of undifferentiated myoblast cells. When adult myocytes isolated from infarcted rat hearts were co-cultured with post-infarct cardiac c-kit+ cells, ERα stimulation inhibited apoptosis and enhanced survival of these myocytes. These findings suggest that cardiac ERα supports survival of cardiomyocytes through post-infarct cardiac c-kit+ cells, which may contribute to cardioprotection against cardiac injury.