17β-Estradiol Modulates Expression of Low-Voltage-Activated CaV3.2 T-Type Calcium Channel via Extracellularly Regulated Kinase Pathway in Cardiomyocytes

Abstract

T-type Ca2+ channel current (ICa,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 ICa,T in cardiomyocytes. We employed in vivo and in vitro techniques to clarify E2-mediated modulation of heart rate (HR) in ovariectomized rats and ICa,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 ICa,T, whereas in cardiomyocytes treated with 10 nm E2 for 24 h, estrogen receptor-independent down-regulation of peak ICa,T and declination of CaV3.2 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 CaV3.1 mRNA was unaltered by E2 treatment in this study. An ERK-1/2, 5 inhibitor, PD-98059, abolished the effects of E2 on ICa,T and CaV3.2 mRNA as well as Csx/Nkx2.5 mRNA. These findings indicate that E2 decreases CaV3.2 ICa,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. Long-term treatment of cardiomyocytes with 17β-estradiol decreases the T-type Ca2+ channel current of CaV3.2 through activation of ERK-1/2, 5, which is mediated by the suppression of a transcription factor Csx/Nkx2.5.