title: Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes.
abstract: OBJECTIVE
  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 (500 ng/kg/min) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection (10(9) pfu/mouse) rescued the impaired EDR and flow-mediated dilatation (FMD) in db/db mice. Diminazene aceturate treatment (15 mg/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-H2DCFDA 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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. Antioxid.
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Yang
authors: Y
authors: Zhang
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Jian
authors: J
authors: Liu
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Jiang-Yun
authors: JY
authors: Luo
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Xiao Yu
authors: XY
authors: Tian
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Wai San
authors: WS
authors: Cheang
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|3 School of Life Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Jian
authors: J
authors: Xu
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Chi Wai
authors: CW
authors: Lau
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Li
authors: L
authors: Wang
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|4 Department of Cardiovascular Sciences, Houston Methodist Research Institute , Houston, Texas.
authors: Wing Tak
authors: WT
authors: Wong
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Chi Ming
authors: CM
authors: Wong
authors: 5 Department of Medicine and Therapeutics, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Hui Yao
authors: HY
authors: Lan
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Xiaoqiang
authors: X
authors: Yao
authors: 6 Department of Physiology and Functional Genomics, University of Florida , Gainesville, Florida.
authors: Mohan K
authors: MK
authors: Raizada
authors: 1 Institute of Vascular Medicine, Chinese University of Hong Kong , Hong Kong SAR, China .|2 Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong SAR, China .
authors: Yu
authors: Y
authors: Huang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000803:Angiotensin I / Q000502:physiology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004133:Diminazene / Q000494:pharmacology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology; D015854:Up-Regulation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D000109:Acetylcholine; D004133:Diminazene