[en] Corticosteroids have been shown to exert beneficial effects in the treatment of acute myocardial infarction, but the precise mechanisms underlying their protective effects are unknown. Here we show that high-dose corticosteroids exert cardiovascular protection through a novel mechanism involving the rapid, non-transcriptional activation of endothelial nitric oxide synthase (eNOS). Binding of corticosteroids to the glucocorticoid receptor (GR) stimulated phosphatidylinositol 3-kinase and protein kinase Akt, leading to eNOS activation and nitric oxide dependent vasorelaxation. Acute administration of pharmacological concentrations of corticosteroids in mice led to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury. These beneficial effects of corticosteroids were abolished by GR antagonists or eNOS inhibitors in wild-type mice and were completely absent in eNOS-deficient (Nos3(-/-)) mice. The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy.
Hafezi-Moghadam, Ali; Harvard Medical School > Pathology
Simoncini, Tommaso; University of Pïsa > Reproductive Medicine and Child Development
Yang, Zequan; University of Vriginia > Biomedial Engineering
Limbourg, Florian P; Brigham & Women's Hospital and Harveard Medical School > Medicine
Plumier, Jean-Christophe ; Université de Liège - ULiège > Département des sciences et gestion de l'environnement > Ecophysiologie et physiologie animale
Rebsamen, Michael C; Brigham & Women's Hospital and Harvard Medical School > Medicine
Hsieh, Chung-Ming; Brigham & Women's Hospital and Harvard Medical School > Medicine
Chui, Dao-Shan; Brigham & Women's Hospital and Harvard Medical School > Medicine
Thomas, Kennard L; Harvard Medical School and University of Virginia
Prorock, Alyson J; University of Virginia > Biomedical Engineering
Laubach, Victor E; University of Virginia > Surgery
Moskowitz, Michael A; Massachusetts General Hospital and Harvard Medical School
French, Brent A; University of Virginia > Biomedical Engineering
Ley, Klaus; University of Virginia > Biomedical Engineering
Liao, James K; Brigham & Women's Hospital and Harvard Medical School > Medicine > Vascula Medicine
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