Protective Role of Progesterone Against BPA-Induced Cardiac Arrhythmias in Female Rat Hearts Via Activation of Rapid Signaling

Presentation Number: FRI 108
Date of Presentation: April 1st, 2016

Jianyong Ma*1 and Hong-Sheng Wang2
1University of Cincinnati, 2University of Cincinnati, OH

Abstract

Bisphenol A (BPA) is a common estrogenic endocrine disruptor that has adverse effects on cardiovascular system. Previously we showed that acute exposure to BPA promoted arrhythmias in female rat hearts mediated by estrogen receptor β signaling. Sex hormones can have complementary or antagonistic actions in many physiology and pathology activities. In view of the known antagonistic interactions between estrogen and progesterone (P4), in this study we investigated the potential protective effect of P4 against the pro-arrhythmic adverse impact of BPA exposure. We showed that acute exposure to BPA resulted in arrhythmogenic triggered activities in female rat ventricular myocytes, and P4 at physiological concentration (1 nM) markedly reduced such aberrant excitations. BPA-induced triggered activities were mediated by increased sarcoplasmic reticulum Ca2+ leak and Ca2+ load; both were found to be normalized by P4. The molecular mechanisms underlying these effects of P4 involved inhibition of BPA-induced increase in the CAMKII phosphorylation of phospholamban (PLN) at Thr 17. At myocyte and protein level, the inhibitory/protective effects of P4 were abolished by pretreatment with nuclear P4 receptor (nPR) antagonist, U486. Analysis using membrane impermeable BSA-conjugated P4 indicated that the actions of P4 were mediated by membrane initiated signaling. The signaling mechanism underlying the P4’s effects involved activation of Src and PI3K, and likely depletion of PIP2, which suppressed BPA-induced IP3 production and activation of CAMKII. These findings suggest that P4 has protective effect against the pro-arrhythmic cardiac toxicity of BPA through activation of non-genomic rapid signaling. Our findings may provide potential therapeutic strategies against the arrhythmogenic toxicity of BPA exposure in female hearts.

 

Nothing to Disclose: JM, HSW