TY - JOUR
T1 - Nitroglycerin drives endothelial nitric oxide synthase activation via the phosphatidylinositol 3-kinase/protein kinase B pathway
AU - Mao, Mao
AU - Sudhahar, Varadarajan
AU - Ansenberger-Fricano, Kristine
AU - Fernandes, Denise C.
AU - Tanaka, Leonardo Y.
AU - Fukai, Tohru
AU - Laurindo, Francisco R.M.
AU - Mason, Ronald P.
AU - Vasquez-Vivar, Jeannette
AU - Minshall, Richard D.
AU - Stadler, Krisztian
AU - Bonini, Marcelo G.
N1 - Funding Information:
The authors are indebted to Drs. Asrar Malik and Xiaopei Gao for the generous gifts of PI3Kp110γ-knockout mice and mouse endothelial cells. We thank Dr. Ann Motten for the careful review of the manuscript. These studies were supported in part by the National Institute of Environmental Health Sciences Division of Intramural Research, an American Heart Association Scientist Development grant (09SDG2250933 to M.G.B.), and a National Heart Lung and Blood grant (R01 HL070187 to T.F.). The authors also thank the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Pesquisa de Desenvolvimento Cientifico e Tecnologico for financial support to F.R.M.L.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - Nitroglycerin (GTN) has been clinically used to treat angina pectoris and acute heart episodes for over 100 years. The effects of GTN have long been recognized and active research has contributed to the unraveling of numerous metabolic routes capable of converting GTN to the potent vasoactive messenger nitric oxide. Recently, the mechanism by which minute doses of GTN elicit robust pharmacological responses was revisited and eNOS activation was implicated as an important route mediating vasodilation induced by low GTN doses (1-50 nM). Here, we demonstrate that at such concentrations the pharmacologic effects of nitroglycerin are largely dependent on the phosphatidylinositol 3-kinase, Akt/PKB, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signal transduction axis. Furthermore, we demonstrate that nitroglycerin- dependent accumulation of 3,4,5-InsP 3, probably because of inhibition of PTEN, is important for eNOS activation, conferring a mechanistic basis for GTN pharmacological action at pharmacologically relevant doses.
AB - Nitroglycerin (GTN) has been clinically used to treat angina pectoris and acute heart episodes for over 100 years. The effects of GTN have long been recognized and active research has contributed to the unraveling of numerous metabolic routes capable of converting GTN to the potent vasoactive messenger nitric oxide. Recently, the mechanism by which minute doses of GTN elicit robust pharmacological responses was revisited and eNOS activation was implicated as an important route mediating vasodilation induced by low GTN doses (1-50 nM). Here, we demonstrate that at such concentrations the pharmacologic effects of nitroglycerin are largely dependent on the phosphatidylinositol 3-kinase, Akt/PKB, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signal transduction axis. Furthermore, we demonstrate that nitroglycerin- dependent accumulation of 3,4,5-InsP 3, probably because of inhibition of PTEN, is important for eNOS activation, conferring a mechanistic basis for GTN pharmacological action at pharmacologically relevant doses.
KW - Akt
KW - Free radicals
KW - Glyceryl trinitrate
KW - Nitric oxide
KW - Nitroglycerin
KW - PI3K
KW - eNOS
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U2 - 10.1016/j.freeradbiomed.2011.09.020
DO - 10.1016/j.freeradbiomed.2011.09.020
M3 - Article
C2 - 22037515
AN - SCOPUS:84855460214
SN - 0891-5849
VL - 52
SP - 427
EP - 435
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -