Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice.
The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10 mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT(1)R) and NAD(P)H oxidase subunits (p22(phox) and p47(phox)), and reduced reactive oxygen species (ROS) production. Acute exposure to AT(1)R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level > or =7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT(1)R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients.
Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, China.
Wing Tak
WT
Wong
Xiao Yu
XY
Tian
Aimin
A
Xu
Chi Fai
CF
Ng
Hung Kay
HK
Lee
Zhen Yu
ZY
Chen
Chak Leung
CL
Au
Xiaoqiang
X
Yao
Yu
Y
Huang
D000369:Aged, 80 and over; D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012084:Renin-Angiotensin System
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D005947:Glucose