Abstract
Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17β-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERβ against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac-hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast. However, overexpression of ERβ and/or administration of E2 inhibited ISO-induced hypertrophy in H9c2 cells. In addition, E2/ERβ also inhibited ISO-induced NFATc3 translocation, and reduced the protein level of downstream marker, BNP. Furthermore, by testing with the calcineurin inhibitor (CsA), it was confirmed that calcineurin acted as a key mediator for the anti-hypertrophic effect of E2/ERβ. In cells treated with calcium blocker (BATPA), the inhibitory effect of E2/ERβ on ISO-induced Ca2+ influx and hypertrophic effects were totally blocked suggesting that E2/ERβ inhibited calcineurin activity to activate I-1 protein and suppress PP1, then induce PLB protein phosphorylation and activation, resulting in Ca2+ reuptake into sarcoplasmic reticulum through SR Ca2+ cycling modification. In conclusion, E2/ERβ suppresses the Ca2+ influx and calcineurin activity induced by ISO to enhance the PLB protein activity and SR Ca2+ cycling.
Highlights
According to the World Health Organization statistics, heart disease is the most common cause of disease-related death worldwide
Further confirmation by western blot expression analysis showed the levels of the hypertrophy markers such as brain natriuretic peptide (BNP) and Atrial natriuretic peptide (ANP) were elevated with the 24 h ISO treatment (Fig 1A)
sympathetic nervous system (SNS) inhibition in cardiomyopathy provides a therapeutic direction for the administration of β-adrenergic receptor (β-AR) blockers in patients with heart failure
Summary
According to the World Health Organization statistics, heart disease is the most common cause of disease-related death worldwide. Heart diseases are markedly more common among men than in women. Incidences of heart disease increases with age, and the increase is sharp among post-menopausal women [1]. Hypertrophy and apoptosis in cardiomyocytes is known to contribute to progression of heart failure, arrhythmias. Angiotensin II (Ang II), βadrenergic receptor agonist, norepinephrine and other hormones play roles in inducing cardiac hypertrophy [2,3,4]. Calcium regulates longer-term effects such as hypertrophy or apoptosis by excitation-transcription coupling [5] Under ISO or AngII stimulation, calcium ions activate calcineurin and dephosphorylate p-NFAT3, which leads to the transactivation of ANP and BNP [6,7]
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