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Upregulation of angiotensin (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes
Zhang Y.1; Liu J.1; Luo J.-Y.1; Tian X.Y.1; Cheang W.S.1; Xu J.1; Lau C.W.1; Wang L.1; Wong W.T.1; Wong C.M.1; Lan H.Y.1; Yao X.1; Raizada M.K.2; Huang Y.1
2015-10-10
Source PublicationAntioxidants and Redox Signaling
ISSN15577716 15230864
Volume23Issue:11Pages:880-892
Abstract

Aims: Angiotensin-converting enzyme 2 (ACE2)-angiotensin (1-7) [Ang (1-7)]-Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical renin-angiotensin system. We sought to study the hypothesis that upregulation of ACE2-Ang (1-7) signaling protects endothelial function through reducing oxidative stress that would result in beneficial outcome in diabetes. Results: Ex vivo treatment with Ang (1-7) enhanced endothelium-dependent relaxation (EDR) in renal arteries from diabetic patients. Both Ang (1-7) infusion via osmotic pump (500ng/kg/min) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection (10 pfu/mouse) rescued the impaired EDR and flow-mediated dilatation (FMD) in db/db mice. Diminazene aceturate treatment (15mg/kg/day) activated ACE2, increased the circulating Ang (1-7) level, and augmented EDR and FMD in db/db mouse arteries. In addition, activation of the ACE2-Ang (1-7) axis reduced reactive oxygen species (ROS) overproduction determined by dihydroethidium staining, CM-HDCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang (1-7) upregulation on endothelial function were confirmed in ACE2 knockout (ACE2 KO) mice both ex vivo and in vitro. Innovation: We elucidate that the ACE2-Ang (1-7)-Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice, especially in diabetic human arteries. Conclusion: Endogenous ACE2-Ang (1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress, suggesting the therapeutic potential of ACE2-Ang(1-7) axis activation against diabetic vasculopathy.

DOI10.1089/ars.2014.6070
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000363964600002
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Cited Times [WOS]:32   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Chinese University of Hong Kong
2.University of Florida
3.Methodist Hospital Houston
Recommended Citation
GB/T 7714
Zhang Y.,Liu J.,Luo J.-Y.,et al. Upregulation of angiotensin (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes[J]. Antioxidants and Redox Signaling,2015,23(11):880-892.
APA Zhang Y..,Liu J..,Luo J.-Y..,Tian X.Y..,Cheang W.S..,...&Huang Y..(2015).Upregulation of angiotensin (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes.Antioxidants and Redox Signaling,23(11),880-892.
MLA Zhang Y.,et al."Upregulation of angiotensin (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes".Antioxidants and Redox Signaling 23.11(2015):880-892.
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