Molnar Gergö A, Lindschau Carsten, Dubrovska Galyna, Mertens Peter R, Kirsch Torsten, Quinkler Marcus, Gollasch Maik, Wresche Stefanie, Luft Friedrich C, Muller Dominik N, Fiebeler Anette
Medical Faculty of the Charite, Experimental and Clinical Research Center and Max DelbrückCenter, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany.
Hypertension. 2008 May;51(5):1372-8. doi: 10.1161/HYPERTENSIONAHA.107.105718. Epub 2008 Mar 17.
Mineralocorticoid receptor blockade protects from angiotensin II-induced target-organ damage. 11beta-Hydroxysteroid dehydrogenase type 2 protects the mineralocorticoid receptor from activation by glucocorticoids; however, high glucocorticoid concentrations and absent 11beta-hydroxysteroid dehydrogenase type 2 in some tissues make glucocorticoids highly relevant mineralocorticoid receptor ligands. We investigated the effects of corticosterone (10(-6) to 10(-12) mol/L) on early vascular mineralocorticoid receptor signaling by Western blotting, confocal microscopy, and myography. Corticosterone initiated extracellular signal-regulated kinase 1/2 phosphorylation in rat vascular smooth muscle cells at > or =10(-11) mol/L doses. Protein synthesis inhibitors had no effect, indicating a nongenomic action. Corticosterone also stimulated c-Jun N-terminal kinase, p38, Src, and Akt phosphorylation at 15 minutes and enhanced angiotensin II-induced signaling at 5 minutes. A specific epidermal growth factor receptor blocker, AG1478, as well as the Src inhibitor PP2, markedly reduced corticosterone-induced extracellular signal-regulated kinase 1/2 phosphorylation, as did preincubation of cells with the mineralocorticoid receptor antagonist spironolactone. Silencing mineralocorticoid receptor with small interfering RNA abolished corticosterone-induced effects. Corticosterone (10(-9) mol/L) enhanced phenylephrine-induced contraction of intact aortic rings. These effects were dependent on the intact endothelium, mineralocorticoid receptor, and mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase signaling. We conclude that corticosterone induces rapid mineralocorticoid receptor signaling in vascular smooth muscle cells that involves mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-dependent pathways. These new mineralocorticoid receptor-dependent signaling pathways suggest that glucocorticoids may contribute to vascular disease via mineralocorticoid receptor signaling, independent of circulating aldosterone.
盐皮质激素受体阻断可预防血管紧张素II诱导的靶器官损伤。2型11β-羟基类固醇脱氢酶可保护盐皮质激素受体不被糖皮质激素激活；然而，高浓度的糖皮质激素以及某些组织中缺乏2型11β-羟基类固醇脱氢酶，使得糖皮质激素成为与盐皮质激素受体高度相关的配体。我们通过蛋白质印迹法、共聚焦显微镜和肌动描记法研究了皮质酮（10⁻⁶至10⁻¹²mol/L）对早期血管盐皮质激素受体信号传导的影响。皮质酮在≥10⁻¹¹mol/L剂量时可引发大鼠血管平滑肌细胞中的细胞外信号调节激酶1/2磷酸化。蛋白质合成抑制剂无作用，表明这是一种非基因组作用。皮质酮在15分钟时还可刺激c-Jun氨基末端激酶、p38、Src和Akt磷酸化，并在5分钟时增强血管紧张素II诱导的信号传导。一种特异性表皮生长因子受体阻滞剂AG1478以及Src抑制剂PP2，与用盐皮质激素受体拮抗剂螺内酯预孵育细胞一样，可显著降低皮质酮诱导的细胞外信号调节激酶1/2磷酸化。用小干扰RNA使盐皮质激素受体沉默可消除皮质酮诱导的效应。皮质酮（10⁻⁹mol/L）增强了去氧肾上腺素诱导的完整主动脉环收缩。这些效应依赖于完整的内皮、盐皮质激素受体以及丝裂原活化蛋白激酶激酶1/细胞外信号调节激酶信号传导。我们得出结论，皮质酮在血管平滑肌细胞中诱导快速的盐皮质激素受体信号传导，这涉及丝裂原活化蛋白激酶激酶/细胞外信号调节激酶依赖性途径。这些新的盐皮质激素受体依赖性信号传导途径表明，糖皮质激素可能通过盐皮质激素受体信号传导导致血管疾病，而与循环醛固酮无关。
