ERα on the cell membrane helps the heart

Abstract

17β-Estradiol is a lipophilic steroid hormone that can pass through the cell's phospholipid membranes and bind to two different classes of estrogen receptors (ERs): the nuclear steroid hormone receptors ERα and ERβ [1] and the G proteincoupled receptor (GPER) also known as the G proteincoupled receptor 30 (GPR30) [2,3]. Hormone binding triggers distinct responses in different tissues through genomic, non-genomic, and combined pathways.The classical ERs are ligand-activated transcription factors. Hormone binding triggers their dimerization, migration to the nucleus, and binding to hormone-response elements on DNA. A separate gene, ESR1 and ESR2, encodes each receptor. ERα and ERβ exhibit significant overall sequence homology, and both are composed of five domains. Since ERα and ERß are co-expressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers. However, there is increasing evidence that ERs are also present on the endothelial cell surface where they can signal in a non-genomic fashion. ERs may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, and receptor tyrosine kinases such as epidermal growth factor (EGFR), insulin-like growth factor (IGF-1), and non-receptor tyrosine kinases such as Src. By interacting with striatin, ERs may influence cytosolic Ca 2+ and nitric oxide. As mentioned, estrogen also binds to GPER resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-triphosphate [3].Endogenous estrogens contribute to the low prevalence of atherosclerotic vascular disease in premenopausal women with intact ovarian function, and cessation of estrogen production following menopause increases cardiovascular risk [4]. Myocardial remodeling, defined as the molecular and cellular events after an injury to the myocardium such as myocardial infarction, is more favorable in women than in men, and estrogen is believed to be responsible [5]. Work presented in this issue of J Mol Med may bring us a little closer to the mechanisms involved [6]. Lee et al. present an evidence that membrane ERα attenuates myocardial fibrosis via Ras homolog member A (RhoA) and Rho-associated, coiled-coil containing protein kinase 1 (ROCK)-mediated actin remodeling [6,7].The authors ovariectomized (OVX) female Wistar rats. Two weeks later, the left-anterior descending coronary artery was ligated, a standard myocardial infarction model. The rats were then assigned to placebo or the implantation of a 60-day release pellet of 17β-estradiol. Four weeks were allowed to pass to permit remodeling to be completed in intact female rats that have endogenous estrogen, OVX rats that have no estrogen, or OVX rats receiving replacement 17β-estradiol. The collagen area fraction was twice as large in the estrogen-deficient OVX group than in the two groups with estrogen, a finding that was verified by measuring the proline content. RhoA was more phosphorylated in the OVX controls than in the two groups with estrogen...

WJ‑MSCs intervention may relieve intrauterine adhesions in female rats via TGF‑β1‑mediated Rho/ROCK signaling inhibition

“…Notably, estrogen has been reported to suppress the progression of fibrosis in myofibroblasts with decreased collagen expression by inhibiting TGF-β1 and the Rho/ROCK signaling pathways (40). In addition, estradiol attenuated myocardial fibrosis by suppressing the RhoA/ ROCK/cofilin pathway in ovariectomized female infarcted rats (41,42). Similarly, in the present study, the expression levels of TGF-β1 and RhoA/ROCKI were inhibited in IUA model rats after WJ-MSCs + estrogen treatment.…”

Atlas of tissue renin-angiotensin-aldosterone system in human: A transcriptomic meta-analysis

“…Third, the cell response where there was a strong core group of receptors GR-MR-AGTR1 which provide cell sensitivity. Although strong inter-relationships have been previously described for receptors 28 29 30 31 , it is the first time that these relationships are detected for extRAAS enzymes. A major difference also appeared between peptide and steroid hormones.…”

Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

“…The large amount of saturated/monounsaturated neutral DAG produced at fertilization may be involved in other fertilization events: protein binding and activation, and membrane fusion events (e.g., fusion of sperm acrosome-plasma membrane, sperm-egg, cortical granulezygote plasma membrane, vesicle-nascent nuclear envelope)(Frohman, 2014; Stith et al, 1997). …”