Mouse Models for Atherosclerosis and Pharmaceutical Modifiers

Zadelaar, Susanne; Kleemann, Robert; Verschuren, Lars; Weij, Jitske de Vries-van der; Hoorn, José van der; Princen, H.M.G.; Kooistra, Teake

doi:10.1161/atvbaha.107.142570

Cited by 478 publications

(443 citation statements)

References 158 publications

(153 reference statements)

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“…They are reported to have antioxidant effects in vascular cells and platelets by inhibiting NOX2 39, 40. Nevertheless, two thirds of statin‐treated patients still experience adverse coronary events that have unclear mechanisms 41, 42…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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“…Mice lack cholesteryl ester transfer protein 47 , they require genetic manipulation in order to develop human-like atherosclerosis 48,49 , and produce a different bile acid pool than humans 45 . Despite these limitations, a diverse set of genetic tools exist for working with mice which make them a good first in vivo model, even for atherosclerosis studies 50 . In this manuscript we provided preliminary evidence suggesting that murine Pgp may be required for to maintain gallbladder bile homeostasis in mice that consumed elevated dietary fat and/or cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

et al. 2013

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P-glycoprotein (Pgp, encoded by ABCB1, commonly known as MDR1), an ATP-dependent transporter with a broad range of hydrophobic drug substrates, has been associated with the in vitro intracellular transport of cholesterol; however, these findings have not been confirmed in vivo. In this manuscript we tested the contributions of Pgp to in vivo cholesterol homeostasis by comparing the cholesterol phenotype of wild type mice with mice lacking both murine isoforms of Pgp (Abcb1a −/− /1b −/− ) by measuring cholesterol absorption, circulating cholesterol, and lipoprotein cholesterol profiles. The mice were fed diets containing normal or high levels of dietary fat (25% vs. 45% kcal from fat) and cholesterol (0.02% vs. 0.20% w/w) for 8 weeks to challenge their capacity to maintain homeostasis.There were no significant differences in cholesterol absorption, circulating cholesterol levels, and lipoprotein profiles between Pgp knockout and wild type mice fed matching diets. Compensatory shifts were observed in the activation of two key transcription factors involved in maintaining cholesterol balance, the Liver X Receptor and SREBP-2, which may have maintained the wild type phenotype in the knockout mice. Deletion of Pgp affected the molar composition of gallbladder bile when the mice were fed diets containing high levels of dietary fat, cholesterol, or both. The mole fraction of bile salts was reduced in the gallbladder bile of Pgp knockout mice while the mole fraction of cholesterol was increased.In this paper, we provide evidence that Pgp knockout mice maintain cholesterol homeostasis, even when challenged with high cholesterol diets. We suggest that the specific shifts in cholesterol regulatory networks identified in the jejunum and liver of the knockout mice may have compensated for the lack of Pgp. Our finding that Pgp knockout mice were unable to maintain

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“…Instead, the inhibition of lp-PLA2 attenuates the in vivo inflammatory burden and decreases atherosclerotic plaque formation in LDLR-deficient mice. Specific gene-knockout mouse models are extensively used to study the pathological processes and pharmacological interventions of atherosclerosis, among which the model of the LDLR-deficient mouse is well established [18] . As the uptake of lipoprotein particles is impaired, the blood lipid profiles of these mice spontaneously rise.…”

Section: Discussionmentioning

confidence: 99%

The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis in LDLR-deficient mice

Zhang

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the effects of darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA2), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice. Methods: Six-week-old LDLR-deficient mice were fed an atherogenic high-fat diet for 17 weeks and then randomly divided into two groups. One group was administered darapladib (50 mg·kg -1 ·d -1 ; po) for 6 weeks. The other group was administered saline as a control. Serum lipid levels were measured using the corresponding kits, and three inflammatory markers -interleukin-6 (IL-6), C reactive protein (hs-CRP), and platelet activating factor (PAF) -were determined using ELISA. Atherosclerotic plaque areas were stained with Sudan IV, and inflammatory gene expression at the lesions was evaluated using quantitative real-time PCR. Results: The body weight and serum lipid level between the two groups were similar at the end of the dietary period. The serum lp-PLA2 activity, hs-CRP and IL-6 levels, however, were significantly reduced in the darpladib group. The inhibition of lp-PLA2 did not alter the serum PAF level. Furthermore, the plaque area, from the aortic arch to the abdominal aorta, was significantly reduced in the darpladib group. Additionally, the expression of inflammatory genes monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was significantly reduced at the lesions in the darapladib group. Conclusion: Inhibition of lp-PLA2 by darapladib decreases the inflammatory burden and atherosclerotic plaque formation in LDLRdeficient mice, which may be a new strategy for the treatment of atherosclerosis.

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Mouse Models for Atherosclerosis and Pharmaceutical Modifiers

Cited by 478 publications

References 158 publications

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis in LDLR-deficient mice

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