The effects of renin-angiotensin system inhibition on aortic cholesterol content in cholesterol-fed rabbits

doi:10.1016/S0021-9150(96)05942-4

Atherosclerosis

Volume 127, Issue 1, 15 November 1996, Pages 123-129

https://doi.org/10.1016/S0021-9150(96)05942-4 Get rights and content

Abstract

To investigate how the renin-angiotensin system (RAS) might be involved in cholesterol-induced atherosclerosis, we studied the effects of a nonsulhydryl angiotensin converting enzyme (ACE) inhibitor, enalapril, and an angiotensin II receptor antagonist, E-4177, in cholesterol fed rabbits. Japanese white rabbits were randomly divided into four groups with the following dietary regimens: group A (n = 8) received a standard diet; group B (n = 8) had a 0.5% cholesterol diet; group C (n = 8) had a 0.5% cholesterol diet plus enalapril (10 mg/kg/day, p.o.); group D (n = 8) received a 0.5% cholesterol diet plus E-4177 (20 mg/kg/day, p.o.) and were fed these diets for 5 weeks. Enalapril or E-4177 had no significant effect on either the total plasma or the high density lipoprotein (HDL) cholesterol concentrations. However, the aortic cholesterol content in groups C and D was equally significantly less than that in group B. The plasma and aortic ACE activities were significantly reduced only in group C compared with those in the other groups. The aortic ACE mRNA and AT1 mRNA levels were assessed by a reverse transcription polymerase chain reaction (RT-PCR). The aortic ACE mRNA level was only significantly less in group C than in any of the other groups. The aortic AT1 mRNA level increased significantly in group B compared with that in group A and was significantly and equally reduced in both groups C and D compared with that in group B. These data indicate that angiotensin II rather than ACE may therefore be related to aortic cholesterol content. It follows therefore that the inhibition of angiotensin II by either ACE inhibitor or angiotensin II (type 1) receptor antagonist may play a role in prevention of atherosclerosis.

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Citation Excerpt :
Epidemiological and experimental studies have shown that ACE inhibitors had a beneficial effect in early atherosclerosis in addition to their antihypertensive activity (Chobanian, Haudenschild, Nickerson, & Drago, 1990; Fennessy, Campbell, & Campbell, 1994). Pharmacological studies have also demonstrated that ACE inhibitors could reduce plasma cholesterol in different animal models (Kowala, Grove, & Aberg, 1994; Sugano, Makino, & Yanaga, 1996). More recent studies have reported that protein hydrolysates from several food materials, such as sardinelle (Khaled et al., 2012), fish (Wergedahl, Gudbrandsen, Røst, & Berge, 2009), sesame (Biswas, Dhar, & Ghosh, 2010) and soy (Aoyama, Fukui, Takamatsu, Hashimoto, & Yamamoto, 2000; Zhong, Zhang, Ma, & Shoemaker, 2007) could affect plasma cholesterol concentrations and metabolisms of polyunsaturated fatty acids.
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Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering “direct” effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects.
Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2 mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control.
Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-α, IL-1β, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu.
Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.
Inhibition of the renin-angiotensin system ameliorates genetically determined hyperinsulinemia
2002, European Journal of Pharmacology
This study was performed in order to assess the potentially different effects of the angiotensin-converting enzyme inhibitor captopril and of the angiotensin II receptor antagonist irbesartan on the metabolic syndrome in an animal model. Male NZO/BL6 F1 mice were treated with captopril, irbesartan, or placebo for 10 months: Control animals treated with placebo developed a metabolic syndrome with obesity (55.5+6.3 g), hypertension (146+10 mm Hg), hyperinsulinemia (7.2+5.7 ng/ml), hypercholesterolemia (5.1+0.7 mmol/l), cardiac hypertrophy (269+44 mg) and atherosclerotic plaques in the ascending aorta (3.6+1.5 μm²). Treatment with angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist significantly (p<0.001) reduces hypertension (73+5 and 78+11 mm Hg), cardiac hypertrophy (203+26 and 202+18 mg) and atherosclerosis (2.2+0.9 and 1.8+0.8 μm²). In addition, they prevented the development of obesity (42.2+3.5 and 38.3+2.8 g) and hyperinsulinemia (3.6+1.5 and 1.8+0.4 ng/ml). In conclusion, long-term treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist can ameliorate obesity and hyperinsulinemia in a genetically determined mouse model.
Attenuation of tissue P-selectin and MCP-1 expression and intimal proliferation by AT<inf>1</inf> receptor blockade in hyperlipidemic rabbits
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Angiotensin-II (Ang-II) participates in the development and progression of atherosclerosis by activating type 1 (AT₁) receptors. In vitro studies show that inflammatory factors, such as P-selectin and MCP-1, which can be upregulated by Ang-II, play an important role in atherogenesis. We examined the effect of AT₁ receptor blockade with losartan on the expression of P-selectin and MCP-1 in hypercholesterolemic rabbits. Since AT₁ receptor blockade is associated with feedback upregulation of renin-angiotensin system (RAS), we also examined alterations in plasma Ang-II levels by losartan therapy. Male NZW rabbits were fed regular chow (high cholesterol diet or high cholesterol diet + losartan 25 mg/kg/day). As expected, there was a marked intimal proliferation in association with increase in serum cholesterol (P < 0.001). In addition, there was a modest increase in plasma Ang-II levels (P < 0.05), and a significant increase in the expression of AT₁ receptors, P-selectin and MCP-1 in aortas of high cholesterol diet rabbits. Concurrent administration of losartan with high cholesterol diet attenuated aortic intimal proliferation induced a fivefold increase in plasma Ang-II levels and caused a marked decrease in expression of P-selectin and MCP-1 without change in serum lipid levels and aortic AT₁ receptor expression. These observations in hypercholesterolemic animal models show that AT₁ receptor blockade is associated with modulation of P-selectin and MCP-1 expression concurrent with reduction in intimal proliferation. The rise in plasma Ang-II does not appear to limit the potential beneficial effect of losartan.
Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis
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Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10⁻⁷ M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P<0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [³H]acetate into cholesterol) by up to 90% (P<0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM’s cholesterol synthesis by up to 70% (P<0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10⁻⁷ M Ang II for 18 h at 37°C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10⁻⁵ M), an AT1 blocker, but not PD 123319 (10⁻⁵ M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose–dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.
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Preβ HDL are small, protein rich lipoproteins that are predominantly composed of apo A-I, without apo A-II. Preβ HDL are secreted from the liver as nascent HDL and/or are produced in the incubated plasma by cholesteryl ester transfer protein (CETP). However, the role of CETP in the secretion of HDL from the liver has yet to be determined. In the present study, we examined the effect of the suppression of hepatic CETP by antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the secretion of apo A-I using a Hep G2 cell culture. The ODNs against CETP were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for the regulation of liver gene expression. Hep G2 cells were cultured in DMEM supplemented with 10% FBS. After 2 days, the medium was changed to DMEM with EGF and the cells were divided into three groups. The control group received saline, while the sense group was mixed with the sense ODNs complex and the antisense group was mixed with the antisense ODNs complex, respectively, for 2 days. Both the hepatic CETP mRNA and the CETP mass in the medium in the antisense group decreased significantly more than in the sense and the control groups (CETP mass: 1.697±0.410 ng/mg cell protein vs. 2.367±0.22 and 2.360±0.139, n=3 in each determination). In contrast, both the hepatic apo A-I mRNA and the apo A-I mass in the medium in the antisense group were significantly higher than those in the sense and the control groups (apo A-I mass; 1.877±0.215 μg/mg cell protein vs. 1.213±0.282 and 1.097±0.144, n=3 in each determination). The increase in apo A-I was mainly due to the increase in preβ apo A-I. These findings may partly explain why HDL and apo A-I increase in patients with CETP deficiency, while also indicating the possibility that the original level of preβ HDL is sufficient in such patients.

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Research paperThe effects of renin-angiotensin system inhibition on aortic cholesterol content in cholesterol-fed rabbits

Abstract

Atherosclerosis

J Lipid Res

Anal Biochem

J Mol Cell Cardiol

Atherosclerosis

J Pharmacol Exp Ther

Remodelling of the vascular system in response to hypertension and drug therapy

Clin Exp Pharmacol Physiol

Biology of disease. The pathogenesis of atherogenesis: atherogenesis and inflammation

Lab Invest

Antiatherogenic effect of captopril in Watanabe heritable hyperlipidemic rabbit

Hypertension

Effects of captopril on atherosclerosis in cynomolgus monkeys

J Cardiovasc Pharmacol

Effect of perindopril on the development of atherosclerosis in the cholesterol-fed rabbits

Clin Exp Pharmacol Physiol

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: II. Effect on regression of atherosclerosis and restoration of endothelial function

J Cardiovasc Pharmacol

Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall

Circ Res

Angiotensin and cell growth: a link to cardiovascular hypertrophy?

J Hypertens

Research paper
The effects of renin-angiotensin system inhibition on aortic cholesterol content in cholesterol-fed rabbits