title: Oestrogen upregulates L-type Ca²⁺ channels via oestrogen-receptor- by a regional genomic mechanism in female rabbit hearts.
abstract: In type-2 long QT (LQT2), adult women and adolescent boys have a higher risk of lethal arrhythmias, called Torsades de pointes (TdP), compared to the opposite sex. In rabbit hearts, similar sex- and age-dependent TdP risks were attributed to higher expression levels of L-type Ca(2+) channels and Na(+)-Ca(2+) exchanger, at the base of the female epicardium. Here, the effects of oestrogen and progesterone are investigated to elucidate the mechanisms whereby I(Ca,L) density is upregulated in adult female rabbit hearts. I(Ca,L) density was measured by the whole-cell patch-clamp technique on days 0-3 in cardiomyocytes isolated from the base and apex of adult female epicardium. Peak I(Ca,L) was 28% higher at the base than apex (P < 0.01) and decreased gradually (days 0-3), becoming similar to apex myocytes, which had stable currents for 3 days. Incubation with oestrogen (E2, 0.1-1.0 nm) increased I(Ca,L) (∼2-fold) in female base but not endo-, apex or male myocytes. Progesterone (0.1-10 μm) had no effect at base myocytes. An agonist of the α- (PPT, 5 nm) but not the β- (DPN, 5 nm) subtype oestrogen receptor (ERα/ERβ) upregulated I(Ca,L) like E2. Western blots detected similar levels of ERα and ERβ in male and female hearts at the base and apex. E2 increased Cav1.2α (immunocytochemistry) and mRNA (RT-PCR) levels but did not change I(Ca,L) kinetics. I(Ca,L) upregulation by E2 was suppressed by the ER antagonist ICI 182,780 (10 μm) or by inhibition of transcription (actinomycin D, 4 μm) or protein biosynthesis (cycloheximide, 70 μm). Therefore, E2 upregulates I(Ca,L) by a regional genomic mechanism involving ERα which is a known determinant of sex differences in TdP risk in LQT2.
authors: University of Pittsburgh, Department of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA.
authors: Xiaoyan
authors: X
authors: Yang
authors: Guojun
authors: G
authors: Chen
authors: Rita
authors: R
authors: Papp
authors: Donald B
authors: DB
authors: Defranco
authors: Fandian
authors: F
authors: Zeng
authors: Guy
authors: G
authors: Salama
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D012727:Sex Characteristics
chemical_list: D020746:Calcium Channels, L-Type; D047628:Estrogen Receptor alpha; D004967:Estrogens; C419385:L-type calcium channel alpha(1C); D011372:Progestins; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol