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

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 6

Effect of nicotinic acid on gene expression and macrophage recruitment in WT and Gpr109a–/– mice.

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Effect of nicotinic acid on gene expression and macrophage recruitment i...
(A) Peritoneal macrophages from WT or GPR109A-deficient mice (Gpr109a–/–) were treated for 4 hours without or with 100 μM nicotinic acid and 20 μg/μl IFN-γ as indicated, and expression of MCP-1 mRNA was determined (mean values ± SEM [n = 6]). (B and C) MCP-1 expression in plaque macrophages (B) and expression of arginase-1 and arginase-2 in the CD68-postitive area (C) in untreated and nicotinic acid–treated atherosclerotic mice (mean ± SEM; n = 5 mice). (D) MCP-1–induced recruitment of peritoneal macrophages. Shown are mean values ± SEM (n = 6). (E) Homing of WT and GPR109A-deficient (Gpr109a–/–) macrophages into atherosclerotic lesions. Shown is the number of macrophages homing into lesions of the aortic root 2 days after intravenous injection in the absence or presence of nicotinic acid. (F) CD68-positive macrophages in lesions of aortic roots from untreated and nicotinic acid–treated Ldlr–/–;Gpr109a+/+ or Ldlr–/–;Gpr109a–/– mice. Shown are data from at least 5 different animals (mean values ± SEM). (G) VCAM-1, ICAM-1, and P-selectin mRNA levels in aortae of Ldlr–/– mice that had been transplanted with Gpr109a+/+ or Gpr109a–/– bone marrow. Animals were kept on a high-fat diet for 16 weeks and were treated without or with nicotinic acid (mean values ± SEM [n ≥ 6]). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.