Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase.
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
A
The Center for Blood Research, Harvard Medical School, Boston, Massachusetts, USA.
Simoncini
Tommaso
T
Yang
Zequan
Z
Limbourg
Florian P
FP
Plumier
Jean-Christophe
JC
Rebsamen
Michael C
MC
Hsieh
Chung-Ming
CM
Chui
Dao-Shan
DS
Thomas
Kennard L
KL
Prorock
Alyson J
AJ
Laubach
Victor E
VE
Moskowitz
Michael A
MA
French
Brent A
BA
Ley
Klaus
K
Liao
James K
JK
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011189:Potassium Chloride
D000305:Adrenal Cortex Hormones; D002316:Cardiotonic Agents; D011189:Potassium Chloride; D003907:Dexamethasone; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester