TY - JOUR
T1 - NADPH Oxidase 1 Plays a Key Role in Diabetes Mellitus-Accelerated Atherosclerosis
AU - Gray, Stephen P.
AU - Di Marco, Elyse
AU - Okabe, Jun
AU - Szyndralewiez, Cedric
AU - Heitz, Freddy
AU - Montezano, Augusto C.
AU - de Haan, Judy B.
AU - Koulis, Christine
AU - El-Osta, Assam
AU - Andrews, Karen L.
AU - Chin-Dusting, Jaye P. F.
AU - Touyz, Rhian M.
AU - Wingler, Kirstin
AU - Cooper, Mark E.
AU - Schmidt, Harald H. H. W.
AU - Jandeleit-Dahm, Karin A.
PY - 2013/5/7
Y1 - 2013/5/7
N2 - Background-In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis. Methods and Results-Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development. Conclusions-These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis. (Circulation. 2013;127:1888-1902.)
AB - Background-In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis. Methods and Results-Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development. Conclusions-These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis. (Circulation. 2013;127:1888-1902.)
KW - atherosclerosis
KW - diabetes mellitus
KW - NADPH oxidase
KW - oxidative stress
U2 - 10.1161/CIRCULATIONAHA.112.132159
DO - 10.1161/CIRCULATIONAHA.112.132159
M3 - Article
C2 - 23564668
SN - 0009-7322
VL - 127
SP - 1888
EP - 1902
JO - Circulation
JF - Circulation
IS - 18
ER -