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

Abstract

T-type Ca(2+) 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 17beta-estradiol (E(2)) on I(Ca,T) in cardiomyocytes. We employed in vivo and in vitro techniques to clarify E(2)-mediated modulation of heart rate (HR) in ovariectomized rats and I(Ca,T) in cardiomyocytes. Ovariectomy increased HR and E(2) supplement reduced HR in ovariectomized rats. Slowing of E(2)-induced HR was consistent with the deceleration of automaticity in E(2)-treated neonatal cardiomyocytes. Short-term application of E(2) did not have significant effects on I(Ca,T), whereas in cardiomyocytes treated with 10 nm E(2) for 24 h, estrogen receptor-independent down-regulation of peak I(Ca,T) and declination of Ca(V)3.2 mRNA were observed. Expression of a cardiac-specific transcription factor Csx/Nkx2.5 was also suppressed by E(2) treatment for 24 h. On the other hand, expression of Ca(V)3.1 mRNA was unaltered by E(2) treatment in this study. An ERK-1/2, 5 inhibitor, PD-98059, abolished the effects of E(2) on I(Ca,T) and Ca(V)3.2 mRNA as well as Csx/Nkx2.5 mRNA. These findings indicate that E(2) decreases Ca(V)3.2 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 E(2) as a negative chronotropic factor in the heart.

Effects of Raloxifene on Voltage- Dependent T-Type Ca²⁺ Channels in Mouse Spermatogenic Cells

“…These studies are consistent with the recently published data showing that 17 ␤ -estradiol treatment decreases Ca V 3.2 mRNA expression but not the expression of Ca V 3.1 mRNA in neonatal cardiomyocytes [32] .…”

T-type calcium channel expression and function in the diseased heart

“…46 The authors proposed a novel, estrogen receptor independent signal transduction scheme whereby 17β-estradiol suppresses the transcription of both Csx/ Nkx2.5 (a developmental gene transcription factor) and its downstream target, the Ca V 3.2 channel mRNA, which involves the activation of extracellular-related kinase 1/2, 5 (ERK-1/2, 5), a component of the MAPK signaling cascade. The same study also provided compelling evidence for the role of Ca V 3.2 Ca 2+ channels in cardiac pace making (see below).…”

“…54 Negative regulation of Ca V 3.2 mRNA and currents by 17β-estradiol in rats was also associated with decreased heart rate, which was reversed by ovariectomy. 46 Thus, multiple lines of evidence suggest an important role of the Ca V 3.2 T-type channel in pacemaker function, and it would be interesting to address whether similar effects on in vivo pacemaker activity would result from the overexpression of Ca V 3.2 channels in the hearts of transgenic mice.…”

Pharmacologic Effects of 2-Methoxyestradiol on Angiotensin Type 1 Receptor Down-Regulation in Rat Liver Epithelial and Aortic Smooth Muscle Cells

“…Trends in epidemiological studies have suggested that there is a correlation with gender and cardiovascular morbidity and mortality, which is believed to be attributable to cardioprotective actions of select female hormones [8,9]. Nevertheless, two clinical trials involving the direct supplementation of estradiol, the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS), were abandoned due to their increased number of cardiovascular events and failure to reduce cardiovascular risks [10].…”