| Abstract
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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.
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