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17β-Estradiol Modulates Expression of Low-Voltage-Activated Ca_V3.2 T-Type Calcium Channel via Extracellularly Regulated Kinase Pathway in Cardiomyocytes

Department of Pathophysiology Science, Oita University School of Medicine, Yufu, Oita 879-5593, Japan

Address all correspondence and requests for reprints to: Katsushige Ono, M.D., Ph.D., Department of Pathophysiology, Oita University School of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan. E-mail: ono{at}med.oita-u.ac.jp.

T-type Ca²⁺ channel current (I_Ca,T) plays an important role for spontaneous pacemaker activity and is involved in the progression of structural heart diseases. Estrogens are of importance for the regulation of growth and differentiation and function in a wide array of target tissues, including those in the cardiovascular system. The aim of this study was to elucidate the short-term and long-term effects of 17β-estradiol (E₂) on I_Ca,T in cardiomyocytes. We employed in vivo and in vitro techniques to clarify E₂-mediated modulation of heart rate (HR) in ovariectomized rats and I_Ca,T in cardiomyocytes. Ovariectomy increased HR and E₂ supplement reduced HR in ovariectomized rats. Slowing of E₂-induced HR was consistent with the deceleration of automaticity in E₂-treated neonatal cardiomyocytes. Short-term application of E₂ did not have significant effects on I_Ca,T, whereas in cardiomyocytes treated with 10 nM E₂ for 24 h, estrogen receptor-independent down-regulation of peak I_Ca,T and declination of Ca_V3.2 mRNA were observed. Expression of a cardiac-specific transcription factor Csx/Nkx2.5 was also suppressed by E₂ treatment for 24 h. On the other hand, expression of Ca_V3.1 mRNA was unaltered by E₂ treatment in this study. An ERK-1/2, 5 inhibitor, PD-98059, abolished the effects of E₂ on I_Ca,T and Ca_V3.2 mRNA as well as Csx/Nkx2.5 mRNA. These findings indicate that E₂ decreases Ca_V3.2 I_Ca,T through activation of ERK-1/2, 5, which is mediated by the suppression of Csx/Nkx2.5-dependent transcription, suggesting a genomic effect of E₂ as a negative chronotropic factor in the heart.