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Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells
Martina Lukasova, … , Jukka Kero, Stefan Offermanns
Martina Lukasova, … , Jukka Kero, Stefan Offermanns
Published February 7, 2011
Citation Information: J Clin Invest. 2011;121(3):1163-1173. https://doi.org/10.1172/JCI41651.
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Research Article

Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

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Abstract

Nicotinic acid (niacin) is a drug used to reduce the progression of atherosclerosis. Its antiatherosclerotic activity is believed to result from lipid-modifying effects, including its ability to decrease LDL cholesterol and increase HDL cholesterol levels in plasma. Here, we report that in a mouse model of atherosclerosis, we found that nicotinic acid inhibited disease progression under conditions that left total cholesterol and HDL cholesterol plasma levels unaffected. The antiatherosclerotic effect was not seen in mice lacking the receptor for nicotinic acid GPR109A. Surprisingly, transplantation of bone marrow from GPR109A-deficient mice into atherosclerosis-prone animals also abrogated the beneficial effect of nicotinic acid. We detected expression of GPR109A in macrophages in atherosclerotic plaques. In macrophages from WT mice, but not from GPR109A-deficient animals, nicotinic acid induced expression of the cholesterol transporter ABCG1 and promoted cholesterol efflux. Furthermore, activation of GPR109A by nicotinic acid inhibited MCP-1–induced recruitment of macrophages into the peritoneal cavity and impaired macrophage recruitment to atherosclerotic plaques. In contrast with current models, our data show that nicotinic acid can reduce the progression of atherosclerosis independently of its lipid-modifying effects through the activation of GPR109A on immune cells. We conclude therefore that GPR109A mediates antiinflammatory effects, which may be useful for treating atherosclerosis and other diseases.

Authors

Martina Lukasova, Camille Malaval, Andreas Gille, Jukka Kero, Stefan Offermanns

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Figure 1

Effects of nicotinic acid on atherosclerotic plaque development in Ldlr–/– and Ldlr–/–;Gpr109a–/– mice.

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Effects of nicotinic acid on atherosclerotic plaque development in Ldlr–...
(A and C) Representative oil red O–stained aortae (A) and cryosections of mouse aortic roots (C) from untreated and nicotinic acid–treated (NA) Ldlr–/– and Ldlr–/–;Gpr109a–/– mice. (B and D) Mean atherosclerotic lesion areas of the aorta (B) and of sections of the aortic root (D) were determined by computer-assisted image analysis. Data are presented as average lesion size in percentage of the total surface of the aorta or as the absolute lesion area on the aortic root. At an age of 8 weeks, animals were treated with a high-fat diet without or with 0.3% nicotinic acid. After 10 weeks of treatment, animals were sacrificed and analyzed. Animal numbers per group were between 8 and 12. Shown are mean values ± SEM; *P ≤ 0.05 (versus Ldlr–/–-NA and Ldlr–/–;Gpr109a–/–+NA). Scale bars: 300 μm.

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