Abstract 11996: Nicotine Promotes Foam Cell Formation and Atherosclerosis by Receptor-mediated Activation of Cd36
In the USA smoking is associated with 175,000 annual deaths due to cardiovascular disease and 30% of all deaths caused by heart attack. The pathogenic roles of stable compounds in the gas phase of cigarette smoke continue to be investigated. Here we confirmed the pro-atherogenic property of nicotine in vivo and investigated the pathway and mechanism in vitro and in vivo. In human THP1-differentiated macrophages, nicotine at “physiological” concentrations (100 nmol/L) found in smokers’ serum increased mRNA and protein expression of the B scavenger receptor CD36 by 116±19% without affecting the expression of proinflammatory cytokines. These effects of nicotine were mediated by a common signaling pathway dependent on reactive oxygen species, PKCδ phosphorylation and PPARγ. Antioxidants as well as non-cholinergic nicotinic blockers prevented nicotine-induced CD36 upregulation. OxLDL increased expression of CD36 and proinflammatory cytokines including TNF-α, MCP-1, IL6, and CXCL9, by 2-4 fold (all p<0.05); the combination of nicotine with OxLDL increased expression of CD36 and inflammatory cytokines by 3-7 fold (all p<0.05). siRNA knockdown of CD36 significantly reduced mRNA expression of CD36 and the expression of inflammatory genes. Nicotine dose-dependently increased OxLDL uptake (25%), which was prevented by CD36 siRNA. Incubation of macrophages with OxLDL for 72 hours resulted in foam cell formation that was exacerbated by pre-incubation with nicotine in a CD36-dependent manner. Treatment of ApoE-/- mice with physiological concentrations of nicotine markedly enhanced population of peripheral blood inflammatory monocytes and aorta atherosclerotic plaque coverage, effects that were not seen in double KO apoE-/-/CD36-/- mice. Our results show for the first time that physiological levels of nicotine increase the expression of CD36 and downstream atherogenic pathways in macrophages. The results with transgenic double KO ApoE-/- CD36-/- mice suggest that this pathway may account entirely for the pro-inflammatory and pro-atherogenic properties of nicotine. These studies identify nicotine as a critical new cardiovascular risk factor of cigarette smoking and caution against the chronic nicotine delivery programs for smoking cessation.
- © 2012 by American Heart Association, Inc.