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

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Future Lipidology (Impact Factor: 1.08). 12/2008; 3(6):625-636. DOI: 10.2217/17460875.3.6.625
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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.

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Available from: Alan Daugherty, Oct 04, 2015
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    • "Aortic aneurysmal and atherosclerotic diseases may occur coincidently in humans [1-5]. Excessive stimulation of the renin angiotensin system (RAS) has been implicated in many human cardiovascular diseases, including aortic aneurysms and atherosclerosis [6,7]. There are substantial experimental data that excessive RAS activation also promotes these diseases in animal models. "
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    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. DOI:10.1371/journal.pone.0081743 · 3.23 Impact Factor
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    • "Table 1 summarizes the effects of genetic manipulations of components of angiotensin synthesis on development of atherosclerosis in mice. There are many publications that have used pharmacologic inhibition of renin or ACE to demonstrate a role for these enzymes in the development of experimental atherosclerosis [13, 14]. However, there is a paucity of studies using genetic manipulations of the enzymes involved in angiotensin peptide synthesis on atherosclerosis development. "
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    ABSTRACT: The renin angiotensin system (RAS) has profound effects on atherosclerosis development in animal models, which is partially complimented by evidence in the human disease. Although angiotensin II was considered to be the principal effector of the RAS, a broader array of bioactive angiotensin peptides have been identified that have increased the scope of enzymes and receptors in the RAS. Genetic interruption of the synthesis of these peptides has not been extensively performed in experimental or human studies. A few studies demonstrate that interruption of a component of the angiotensin peptide synthesis pathway reduces experimental lesion formation. The evidence in human studies has not been consistent. Conversely, genetic manipulation of the RAS receptors has demonstrated that AT1a receptors are profoundly involved in experimental atherosclerosis. Few studies have reported links of genetic variants of angiotensin II receptors to human atherosclerotic diseases. Further genetic studies are needed to define the role of RAS in atherosclerosis.
    Current Atherosclerosis Reports 05/2010; 12(3):167-73. DOI:10.1007/s11883-010-0109-4 · 3.42 Impact Factor
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    ABSTRACT: Objective: The objective of this paper is to investigate a profile on circulatory renin-angiotensin system (RAS) activity in hypercholesterolemic (HC) patients treated with statins. Methods: Eighteen primary HC patients and 18 sex- and age-matched healthy adults were included in this study as controls. Total cholesterol (TC), triglyceride (TG), LDL-C, blood glucose, angiotensin-converting enzyme (ACE) activity, and angiotensin II (Ang II) levels were measured before and four and eight weeks after beginning statin treatment in the HC group. Similar measurements were taken in the control group at baseline. Results: At baseline, TC, TG and LDL-C levels, as well as ACE activity and Ang II concentrations, were significantly higher in the HC group than in the control group. Based on the baseline data collection of 36 participants, there were significant positive correlations between ACE activity and TC (r = 0.54) or LDL-C (r = 0.51), and between Ang II level and TC (r = 0.34) or LDL-C (r = 0.27). TC, LDL-C, Ang II (35.46 ± 14.49 vs 71.10 ± 20.47 pg/ml, p < 0.05) levels and ACE activity (108.9 ± 51.9 vs 180.1 ± 71.3 U/L, p < 0.05) were decreased in HC patients eight weeks after starting statin treatment. In HC patients, RAS activity correlated positively with TC and LDL-C levels before and after treatment. Conclusions: In HC patients, lowering serum cholesterol with statins is associated with decreased circulatory RAS activity.
    Journal of Renin-Angiotensin-Aldosterone System 03/2013; 16(1). DOI:10.1177/1470320313483349 · 2.40 Impact Factor
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