Article

Augmentation of the renin-angiotensin system by hypercholesterolemia promotes vascular diseases.

University of Kentucky, Wethington Building, Room 521, Lexington, KY 40536-40200, USA, Tel.: +1 859 323 4933 ext. 81389, , .
Future Lipidology (Impact Factor: 0.77). 12/2008; 3(6):625-636. DOI: 10.2217/17460875.3.6.625
Source: PubMed

ABSTRACT Activation of the renin-angiotensin system (RAS) and aberrant cholesterol metabolism have generally been considered as independent mechanisms in the development of several vascular diseases. However, it is becoming increasingly apparent in both human and animal studies that many aspects of the RAS may be augmented by hypercholesterolemia, resulting in enhancement of the severity and occurrence of several vascular diseases, including hypertension, atherosclerosis and abdominal aortic aneurysms. Some potential hypercholesterolemia-induced mechanisms have been demonstrated to increase activity of specific components of the RAS. These include increased AT1-receptor expression, increased responsiveness to Ang II and increased synthesis of angiotensin peptides. Future studies need to validate mechanisms of hypercholesterolemia-induced RAS activation in different vascular diseases.

0 Bookmarks
 · 
115 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to determine effects of amlodipine, a dihydropyridine calcium channel blocker, on development of angiotensin II (AngII)-induced vascular pathologies. Male LDL receptor -/- mice were infused with vehicle, amlodipine (5 mg/kg/d), AngII (1,000 ng/kg/min), or AngII + amlodipine for 4 weeks through osmotic pumps (n=10/group). Mice were fed a saturated fat-enriched diet for 1 week prior to pump implantation and during 4 weeks of infusion. Infusion of amlodipine resulted in plasma concentrations of 32 ± 2 ng/ml and 27 ± 2 ng/ml for mice in saline + amlodipine and AngII + amlodipine groups, respectively. This infusion rate of amlodipine did not affect AngII-induced increases in systolic blood pressure. Three of 10 (30%) mice infused with AngII died of aortic rupture, while aortic rupture did not occur in mice co-infused with AngII + amlodipine. Suprarenal aortic width and intimal area of ascending aortas were measured to define aortic aneurysms. In the absence of AngII infusion, amlodipine did not change suprarenal aortic width and ascending aortic area. Infusion of AngII led to profound increases of suprarenal aortic width (saline + vehicle versus AngII + vehicle: 0.86 ± 0.02 versus 1.72 ± 0.26 mm; P=0.0006), whereas co-infusion of AngII and amlodipine diminished abdominal dilation (1.02 ± 0.14 mm; P=0.003). As expected, AngII infusion increased mean intimal area of ascending aortas (saline + vehicle versus AngII + vehicle: 8.5 ± 0.3 versus 12.5 ± 1.1 mm(2); P=0.001), while co-infusion of AngII and amlodipine ablated dilation of the ascending aorta (8.6 ± 0.2 mm(2); P=0.03). Co-administration of amlodipine also significantly attenuated AngII-induced atherosclerosis in the thoracic region as quantified by percent lesion area (AngII + vehicle versus AngII + amlodipine: 5.8 ± 2.1 % versus 0.3 ± 0.1%; P=0.05). Amlodipine inhibited AngII-induced aortic aneurysms in both the abdominal and ascending regions, and atherosclerosis in hypercholesterolemic mice.
    PLoS ONE 11/2013; 8(11):e81743. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme. To define the contribution of ACE-dependent activity to angiotensin II synthesis in atherosclerotic development, male low-density lipoprotein receptor(-/-) mice were fed a fat-enriched diet and infused with either angiotensin I or angiotensin II. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Coinfusion of an ACE inhibitor, enalapril, ablated angiotensin I-augmented atherosclerosis but had no effect on angiotensin II-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted angiotensin II, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with bone marrow-derived cells from either ACE(+/+) or ACE(-/-) mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches but had no effects in aortic roots. ACE mediates angiotensin I-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice.
    Arteriosclerosis Thrombosis and Vascular Biology 07/2013; · 6.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abdominal aortic aneurysm is associated with infiltration of inflammatory cells into the aortic wall. The inflammatory response is also evident in animal models, such as apolipoprotein E-deficient (ApoE-/-) mice that have been infused with angiotensin II, prior to development of aortic aneurysm. Since omega-3 polyunsaturated fatty acids (n-3 PUFAs) and their metabolites have anti-inflammatory and pro-resolving activity, we hypothesised that dietary supplementation with n-3 PUFAs would protect against inflammatory processes in this mouse model. Twenty C57 and 20 ApoE-/- 3-4 week old male mice were supplemented with a low (0.14%, n = 10/group) or high (0.70%, n = 10/group) n-3 PUFA diet for 8 weeks before 2-day infusion with 0.9% saline or angiotensin II (1000 ng/kg/min). Four ApoE-/- mice on the low n-3 PUFA diet and none of the ApoE-/- mice on the high n-3 PUFA diet showed morphological evidence of abdominal aortic dissection. The plasma concentration of the n-3 PUFA metabolite, resolvin D1 was higher in angiotensin II-infused ApoE-/- mice fed the high, compared to the low n-3 PUFA diet. The number of neutrophils and macrophages infiltrating the abdominal aorta was elevated in ApoE-/- mice on the low n-3 PUFA diet, and this was significantly attenuated in mice that were fed the high n-3 PUFA diet. Most neutrophils and macrophages were associated with dissected aortas. Immunoreactivity of the catalytic subunit of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, Nox2, and superoxide were elevated in ApoE-/- mice that were fed the low n-3 PUFA diet, and this was also significantly attenuated in mice that were fed the high n-3 PUFA diet. Together, the findings indicate that supplementation of ApoE-/- mice with a diet high in n-3 PUFA content protected the mice against pro-inflammatory and oxidative stress responses following short-term infusion with angiotensin II.
    PLoS ONE 11/2014; 9(11):e112816. · 3.53 Impact Factor

Full-text (2 Sources)

Download
40 Downloads
Available from
May 29, 2014