Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt., 98, Debrecen, 4032, Hungary.
Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
Naunyn Schmiedebergs Arch Pharmacol. 2018 Apr;391(4):371-383. doi: 10.1007/s00210-018-1462-z. Epub 2018 Jan 21.
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.
内皮素-1（ET-1）是一种有效的血管收缩剂，通常在维持血管张力方面发挥作用，但当异常表达或调节时，可能会介导重要的致病作用，导致几种严重疾病。本研究评估了 ET-1 影响体外 H9c2 大鼠心肌细胞肥大活性和血红素加氧酶-1（HO-1）表达降低的能力，这与心血管疾病（CVD）的体内过程相对应。β-雌二醇（β-E）用于改变 ET-1 的作用。培养 48 小时的 H9c2 细胞用 100-10000 nM ET-1 刺激，并评估细胞大小、细胞活力和细胞保护热休克蛋白 HO-1 的表达变化，在选定的培养物中加入 200 nM β-E 以评估其对 ET-1 介导的变化的影响。应用 100 至 10000 nM ET-1 可显著增加平均细胞大小，并降低细胞活力和 HO-1 蛋白含量（p<0.05）。此外，观察到 200 nM β-E 可显著拮抗 1000 nM ET-1 刺激的心肌细胞的这些作用（p<0.05）。静脉内给予 1000 ng/kg ET-1 的 Sprague-Dawley 大鼠外周血和左心室组织中 HO-1 表达降低，200 ng/kg β-E 注射拮抗，表明体外和体内效应之间可能存在对应关系。β-E 临床应用于心脏肥大的管理中特别有价值的结果是观察到药物能够减轻 ET-1 介导的 HO-1 表达抑制。先前已经证明，HO-1 诱导剂具有强大的心脏保护特性，因此有望将其与 β-E 结合使用，从而降低药物的有效剂量，同时降低与临床使用相关的不良反应。本研究的主要发现是，用 β-E 预处理心肌细胞可抑制其对 ET-1 的肥大反应，并拮抗细胞活力的降低。这些作用与在体外和体内条件下均恢复 HO-1 蛋白表达有关。
