Inhibitory effects of <i>N</i>‐acetylcysteine on scavenger receptor class A expression in human macrophages

Svensson, L.; Norén, K.; Wiklund, Olov; Lindmark, Helena; Ohlsson, Björn; Hultén, Lillemor Mattsson

doi:10.1046/j.1365-2796.2002.00983.x

Cited by 14 publications

(10 citation statements)

References 48 publications

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“…Therefore, it seems likely that ROS generated from PKC-dependent NAD(P)H oxidase pathway are involved in the high glucose-enhanced SR-A expression. This result is consistent with the previous report that ROS enhance the SR-A expression in human monocyte-derived macrophages (45). In addition, the effective suppression of high glucose-enhanced SR-A expression by extracellular signal-regulated kinase inhibitor (Fig.…”

Section: Discussionsupporting

confidence: 93%

Expression of Class A Scavenger Receptor Is Enhanced by High Glucose in Vitro and under Diabetic Conditions in Vivo

Fukuhara-Takaki

Sakai

Sakamoto

et al. 2005

Journal of Biological Chemistry

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In the early stage of atherosclerosis, macrophages take up chemically modified low density lipoproteins (LDL) through the scavenger receptors, leading to foam cell formation in atherosclerotic lesions. To get insight into a role of the scavenger receptors in diabetes-enhanced atherosclerotic complications, the effects on class A scavenger receptor (SR-A) of high glucose exposure in vitro as well as the diabetic conditions in vivo were determined in the present study. The in vitro experiments demonstrated that high glucose exposure to human monocyte-derived macrophages led to an increased SR-A expression with a concomitant increase in the endocytic uptake of acetylated LDL and oxidized LDL. The endocytic process was significantly suppressed by an anti-SR-A neutralizing antibody. Stability analyses revealed a significant increased stability of SR-A at a mRNA level but not a protein level, indicating that high glucoseinduced up-regulation of SR-A is due largely to increased stability of SR-A mRNA. High glucose-enhanced SR-A expression was prevented by protein kinase C and NAD(P)H oxidase inhibitors as well as antioxidants. High glucose-enhanced production of intracellular peroxides was visualized in these cells, which was attenuated by an antioxidant. The in vivo experiments demonstrated that peritoneal macrophages from streptozotocin-induced diabetic mice increased SR-A expression when compared with those from nondiabetic mice. Endocytic degradation of acetylated LDL and oxidized LDL were also increased with these macrophages but not with the corresponding macrophages from diabetic SR-A knock-out mice. These in vitro and in vivo results probably suggest that reactive oxygen species generated from a protein kinase C-dependent NAD(P)H oxidase pathway plays a role in the high glucose-induced up-regulation of SR-A, leading to the increased endocytic degradation of modified LDL for foam cell formation. This could be one mechanism for an increased rate of atherosclerosis in patients with diabetes.

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Section: Discussionsupporting

confidence: 93%

Expression of Class A Scavenger Receptor Is Enhanced by High Glucose in Vitro and under Diabetic Conditions in Vivo

Fukuhara-Takaki

Sakai

Sakamoto

et al. 2005

Journal of Biological Chemistry

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“…One possible explanation is that NAC may be having direct effects at the receptor level in platelets, as seen in similar studies using human macrophages and vascular smooth muscle cells [24,25]. …”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes

Gibson

Winterburn

Barrett

et al. 2011

Cardiovasc Diabetol

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BackgroundPlatelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione (GSH). Clinical delivery of N-acetylcysteine (NAC), a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes.MethodsBlood samples (n = 13) were incubated (2 h, 37°C) with NAC (10-100 micromolar) in vitro. Platelet aggregation in response to thrombin and ADP (whole blood aggregometry) was assessed, together with platelet GSH concentration (reduced and oxidized), antioxidant status, reactive oxygen species (ROS) generation, and plasma NOx (a surrogate measure of platelet-derived nitric oxide; NO).ResultsAt therapeutically relevant concentrations (10-100 micromolar), NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC.ConclusionsOur results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes.

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“…SR-A isoforms are largely expressed on macrophages but can also be detected on endothelial and VSMCs. 23 SR-A seems to have a pivotal role on foam cell formation, since mice susceptible to diet-induced atherosclerosis and lacking SR-A showed significantly reduced atherosclerotic lesion size. 24 On the other hand, CD36 is expressed in monocytes, macrophages, platelets, endothelium, adipocytes, and VSMCs.…”

Section: Ldl and Atherosclerosis Developmentmentioning

confidence: 94%

LDL‐cholesterol versus HDL‐cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos

Badimon

Vilahur

2012

Annals of the New York Academy of Sciences

154

114

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Atherosclerosis is a complex disease in which many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low-density lipoproteins (LDL) play a main role in the initiation and progression of atherosclerosis. Despite currently available optimal LDL-lowering therapies, a worrisome number of clinical events still occur. The protective effect of high-density lipoproteins (HDL) in atherosclerosis, either by suppressing vascular-LDL accumulation, inflammation, oxidation, endothelial damage, and thrombosis, has supported the need of the use of HDL-raising therapies to address this residual risk. Results obtained in some studies, however, have shown that HDL quality, rather than quantity, should be the target of future pharmacological therapies. Here, we will first explore the mechanism by which excess LDL is fundamental in the development of atherosclerosis and its thrombotic complications, behaving as a factor that introduces chaos in the vascular wall. Afterwards, we will explore how functional HDL, through various cellular and molecular mechanisms, facilitates the resolution of this vascular chaos by suppression of atherosclerosis progression and induction of regression.

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Inhibitory effects of N‐acetylcysteine on scavenger receptor class A expression in human macrophages

Cited by 14 publications

References 48 publications

Expression of Class A Scavenger Receptor Is Enhanced by High Glucose in Vitro and under Diabetic Conditions in Vivo

Expression of Class A Scavenger Receptor Is Enhanced by High Glucose in Vitro and under Diabetic Conditions in Vivo

Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes

LDL‐cholesterol versus HDL‐cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos

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