ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice.
Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.
Cassis
Lisa A
LA
Rm. 521b, Wethington Bldg., Graduate Center for Nutritional Sciences, Univ. of Kentucky, Lexington, KY 40536-0200, USA. lcassis@uky.edu
Gupte
Manisha
M
Thayer
Sarah
S
Zhang
Xuan
X
Charnigo
Richard
R
Howatt
Deborah A
DA
Rateri
Debra L
DL
Daugherty
Alan
A
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D006830:Hydralazine / Q000008:administration & dosage; D006937:Hypercholesterolemia / Q000150:complications* / Q000209:etiology / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology / Q000517:prevention & control; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000008:administration & dosage; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012307:Risk Factors; D013997:Time Factors
D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D000804:Angiotensin II; D006830:Hydralazine; D009638:Norepinephrine