Abstract
Endothelin-1 (ET-1), a potent vasoconstrictor normally active in maintaining vascular tone, may mediate significant pathogenic effects, contributing to several serious diseases when aberrantly expressed or regulated. The present study evaluates the capacity of ET-1 to affect endothelin-1-associated hypertrophic activity and decreased expression of heme oxygenase-1 by H9c2 rat cardiomyoblasts in vitro, corresponding to in vivo processes underlying cardiovascular diseases (CVDs). Beta estradiol (β-E) is tested for its capacity to alter the effects of ET-1. H9c2 cells, cultured 48 h, were stimulated with 100–10,000 nM of ET-1 and evaluated for changes in cell size, cell viability, and expression of the cytoprotective heat shock protein heme oxygenase-1 (HO-1), with 200 nM of β-E included in selected cultures to evaluate its effect on ET-1-mediated changes. The application of 100 to 10,000 nM of ET-1 resulted in a significant increase in average cell size and decreases in both cell viability and HO-1 protein content (p < 0.05). Moreover, 200 nM of β-E was observed to significantly counteract these effects by cardiomyoblasts stimulated with 1000 nM of ET-1 (p < 0.05). Sprague-Dawley rats treated intravenously with 1000 ng/kg of ET-1 demonstrated reduced HO-1 expression in peripheral blood and left ventricular tissue, which was counteracted by injection of 200 ng/kg β-E—demonstrating a possible correspondence between in vitro and in vivo effects. An outcome of particular value for clinical use of β-E, in the management of cardiac hypertrophy, is the observed capacity of the drug to abate ET-1-mediated suppression of HO-1 expression. It has been previously demonstrated that HO-1 inducers exhibit potent cardioprotective properties, thus offering the promise of combining them with β-E, allowing lower effective dosage of the drug and concomitantly lower adverse side effects associated with its clinical use. Major findings of this investigation are that pretreatment of cardiomyoblasts with β-E inhibited their hypertrophic response to ET-1 and counteracts the decrease of cell viability. These effects were associated with a restoration of HO-1 protein expression in both under in vitro and in vivo conditions.
Highlights
Cardiopulmonary and cardiovascular diseases (CVDs) leading to respiratory and heart failure are the major cause of deathNaunyn-Schmiedeberg's Arch Pharmacol (2018) 391:371–383(Stewart et al 2001)
Data presented in this study reveals notably that administration of the hormone following transient middle cerebral artery occlusion occurring as a pathological outcome of intracerebral ET-1 injection resulted in diminished levels of degenerating neurons and lesser infarct zone magnitude, demonstrating a clear neuroprotective effect mediated by β-E
Outcomes are expressed in square micrometers of cell surface area ± standard error of the means (SEM). n = 200 cells in each group. *p < 0.05 with respect to comparisons made to the drug-free control culture (C) value, and +p < 0.05 compared to the average percent cell viability evaluated in the 1000 nM of ET-1 + E group treated with 200 nM of β-E, followed by stimulation with 1000 nM of ET-1, revealed that β-E-mediated significant suppression of cell surface area increase—induced by 1000 nM ET-1
Summary
Cardiopulmonary and cardiovascular diseases (CVDs) leading to respiratory and heart failure are the major cause of deathNaunyn-Schmiedeberg's Arch Pharmacol (2018) 391:371–383(Stewart et al 2001). Pharmacological strategies for decreasing hypertrophic signaling downstream of ET-1 in cardiomyocytes were suggested by findings made previously by the authors that antihypertrophic effects in isolated rat hearts could be achieved by inhibition of calcineurin activity, with resulting reduction of the nuclear translocation of NF-AT, a pro-hypertrophic transcription factor (Haines et al 2000) These experiments did not include the role of β-E in signaling; it was described in a 2015 report that a natural compound called tanshinone IIA inhibited estrogen receptor-mediated cardiomyocyte hypertrophy through enhancement of Akt phosphorylation. Data presented in this study reveals notably that administration of the hormone following transient middle cerebral artery occlusion (tMCAO) occurring as a pathological outcome of intracerebral ET-1 injection resulted in diminished levels of degenerating neurons and lesser infarct zone magnitude, demonstrating a clear neuroprotective effect mediated by β-E These results may demonstrate the potential for management of cardiac hypertrophy in a model that uses ET-1 treatment to induce the effects described. The compound may exert non-genomic effects through interaction with membrane estrogen receptors (mERs), such as estradiol-selective G proteincoupled estrogen receptor (GPER, formerly known as GPR30) (Prossnitz and Barton 2014)
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