Glucocorticoid-related signaling effects in vascular smooth muscle cells.
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.
Molnar
Gergö A
GA
Medical Faculty of the Charite, Experimental and Clinical Research Center and Max DelbrückCenter, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany.
Lindschau
Carsten
C
Dubrovska
Galyna
G
Mertens
Peter R
PR
Kirsch
Torsten
T
Quinkler
Marcus
M
Gollasch
Maik
M
Wresche
Stefanie
S
Luft
Friedrich C
FC
Muller
Dominik N
DN
Fiebeler
Anette
A
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases
D018161:Receptors, Mineralocorticoid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D003345:Corticosterone