Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice.
OBJECTIVE
Endothelial dysfunction is considered a surrogate marker for cardiovascular disease. Angiotensin II, the principal hormone of the renin angiotensin system, is known to promote atherogenesis. However, other angiotensin peptide fragments such as angiotensin IV possess biological activity that may in fact counter-regulate the actions of angiotensin II. Therefore, we investigated the role of angiotensin IV on the development of endothelial dysfunction in apolipoprotein E-deficient (ApoE-/-) mice.


RESULTS
In contrast to their wild-type control, ApoE-/- mice that were fed a high-fat diet had exacerbated endothelial dysfunction, evidenced by impaired endothelium-dependent vasodilation. Chronic infusion of angiotensin IV (1.44 mg/kg per day) in ApoE-/- mice for 2 weeks resulted in significant improvements in endothelial function. Angiotensin IV treatment markedly decreased superoxide levels (dihydroethidium staining fluorescence and L-012 chemiluminescence) and increased endothelial nitric oxide synthase expression (immunoreactivity and western blotting) in aortic tissue. Co-treatment of angiotensin IV with either AT4 receptor antagonist divalinal-Ang IV or AT2 receptor antagonist PD123319 attenuated these changes, indicating involvement of both the AT4 and the AT2 receptors.


CONCLUSIONS
Chronic angiotensin IV treatment in ApoE-/- mice evoked a marked vasoprotective effect that appeared to be mediated by improved NO bioavailability as a result of AT4 and/or AT2 receptor stimulation.
Vinh
Antony
A
Department of Pharmacology, Monash University, Building 13E, Clayton, Victoria 3800, Australia.
Widdop
Robert E
RE
Drummond
Grant R
GR
Gaspari
Tracey A
TA
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D007150:Immunohistochemistry; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000032:analysis / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001057:Apolipoproteins E; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013481:Superoxides; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III