Estrogen receptor activation and cardioprotection in ischemia reperfusion injury

Abstract

Premenopausal females have a comparably lower incidence of cardiovascular disease than their male counterparts. Although estrogen and activation of estrogen receptors (ERs) have been found to contribute to female protection, the complex mechanisms involved are unclear. Besides altering gene transcription, estrogen could elicit its cardioprotective effect via ER-mediated nongenomic signaling pathways. In addition to the two classic nuclear ER isoforms, ERα and ERβ, a G-protein coupled ER (GPR30 or GPER) has been found to be expressed in cardiomyocytes and plays an acute cardioprotective role in ischemia reperfusion injury. By using isoform-specific ER knockout mouse models and/or their specific modulators, the mechanisms of the different ERs involved in cardioprotection have been explored. In this review, we will focus on the signaling pathways leading to cardioprotection in ischemia reperfusion injury after ER activation and discuss the possibility and promise of specific ER modulators to treat ischemic heart diseases.

Figure 1. Cardioprotective signaling pathways via ER activation

(1) Genomic actions of ER activation. Notable changes in gene expression, like modulators of the NO system, have been shown to be upregulated with chronic ERβ stimulation and involved in cardioprotection. (2) Activation of both PI3K/Akt and NO signaling result in cardioprotection and enhanced cell survival. The chronic activation of ERβ by DPN treatment leads to cardioprotection and significant increased S-nitrosylated proteins, including mitochondrial F₁F_0-ATPase (F₁F₀), aconitase (Ac), cytochrome c oxidase (Cyto c Ox), heat shock proteins (HSP27/60/70), creatine kinase (CK), and malate dehydrogenase (MD). (3) A G-protein coupled estrogen receptor, GPR30 or GPER, has been recently demonstrated to result in cardioprotection through a PI3K/Akt pathway. Whether through chronic or acute activation, stimulation of estrogen receptors has been shown to result in a cardioprotective phenotype.