Abstract
BackgroundAT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs), although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.Methods and ResultsMale AT2 receptor wild type (AT2 +/y) and deficient (AT2 -/y) mice in an LDL receptor −/− background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min). AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day) and AngII were co-infused into male LDL receptor −/− mice that were either AT2 +/y or −/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.ConclusionsAT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism.
Highlights
Chronic infusion of angiotensin II (AngII) into hypercholesterolemic mice promotes formation of aortic aneurysms that predominantly localize to the suprarenal aortic (AAAs) and ascending aortic (TAAs) regions and augments atherosclerotic lesions [1,2,3,4]
While we have reported that PD123319 augments AngII-induced abdominal aortic aneurysms (AAAs) [6], there are conflicting findings regarding the effects of PD123319 on atherosclerosis
Since AT2 receptor is located on the X chromosome, male AT2 receptor deficient mice are represented as AT2 -/y, and wild type littermates are denoted as AT2 receptor wild type (AT2 +/y)
Summary
Chronic infusion of angiotensin II (AngII) into hypercholesterolemic mice promotes formation of aortic aneurysms that predominantly localize to the suprarenal aortic (AAAs) and ascending aortic (TAAs) regions and augments atherosclerotic lesions [1,2,3,4]. AT1 receptors are expressed as two subtypes termed AT1a and AT1b. AT1a receptors are the most predominant AngII receptor subtype in many tissues of adult mice, whereas AT2 receptors are abundant in fetal development with expression restricted to adrenal glands, brain, kidneys, and heart of adult rodents [5]. Despite its low expression in many tissues of adult rodents, AT2 receptors are upregulated during vascular injury [8]. AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs), a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms
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