Estrogen Receptor-β Prevents Cardiac Fibrosis

Abstract

Development of cardiac fibrosis portends the transition and deterioration from hypertrophy to dilation and heart failure. Here we examined how estrogen blocks this important development. Angiotensin II (AngII) and endothelin-1 induce cardiac hypertrophy and fibrosis in humans. and we find that these agents directly stimulate the transition of the cardiac fibroblast to a myofibroblast. AngII and endothelin-1 stimulated TGFβ1 synthesis in the fibroblast, an inducer of fibrosis that signaled via c-jun kinase to Sma- and Mad-related protein 3 phosphorylation and nuclear translocation in myofibroblasts. As a result, mesenchymal proteins fibronectin and vimentin were produced, as were collagens I and III, the major forms found in fibrotic hearts. 17β-Estradiol (E2) or dipropylnitrile, an estrogen receptor (ER)β agonist, comparably blocked all these events, reversed by estrogen receptor (ER)β small interfering RNA. E2 and dipropylnitrile signaling through cAMP and protein kinase A prevented myofibroblast formation and blocked activation of c-jun kinase and important events of fibrosis. In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents. Our results establish the cardiac fibroblast as an important target for hypertrophic/fibrosis-inducing peptides the actions of which were mitigated by E2/ERβ acting in these stromal cells.

Intermedin_1–53 Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice

“…The intracellular cAMP/PKA pathway involved in inhibiting the phosphorylation and subsequent degradation of inhibitory κ B (I κ B), leading to decrease of NF- κ B nuclear translocation 51, 52) . Furthermore, in CFs, cAMP/PKA signaling activation by estrogen blocked myofibroblast formation and JNK activation by TGF- β 1 53, 54) . Here, results showed that IMD 1–53 supplementation increased the phosphorylation of PKA and suppressed NF- κ B and JNK activation compared with Hcy alone.…”

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

“…136 While reports using ERKO mice suggest these receptors have important and distinct cardiac roles, these studies are confounded by the systemic effects of global ER deletion, as αERKO mice have increased levels of circulating estrogen, are obese, and insulin resistant, and βERKO mice exhibit hypoxia and hypertension. 137–141 Other models, however, provide evidence of the cardioprotective effects of estrogen. For example, estrogen treatment of OVX rats 24 hours after MI resulted in increased expression of connexin 43, which allowed for critical cell-gap junctions to be maintained and reduced fatal ventricular arrhythmias.…”

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…ERβ plays a key role in cardiac protection,17 and ERα, especially in the endothelium, is involved in the beneficial vascular actions of 17β‐estradiol 18. Indeed, most of the vascular actions of 17β‐estradiol are abrogated in mice lacking ERα in both endothelial and hematopoietic cells by breeding Tie2‐Cre transgenic mice (expressing the Cre recombinase under the control of the endothelial tyrosine‐protein kinase receptor (Tie2) promoter) with ERα‐floxed mice at exon 2 (ERα lox/lox ) 8, 15, 19.…”