Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling

Abstract

Zhou MS, Chadipiralla K, Mendez AJ, Jaimes EA, Silverstein RL, Webster K, Raij L. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. Am J Physiol Heart Circ Physiol 305: H563-H574, 2013. First published June 7, 2013 doi:10.1152/ajpheart.00042.2013.-Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36 ϩ /CD14 ϩ cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKC␦ phosphorylation, and peroxisome proliferator-activated receptor-␥ (PPAR␥) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKC␦ and PPAR␥ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-␣, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 g/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE Ϫ/Ϫ mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36 Ϫ/Ϫ apoE Ϫ/Ϫ mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration.nicotine; CD36; inflammatory cytokine; macrophage; foam cell SMOKING ACCOUNTS FOR 175,000 cardiovascular (CV) deaths annually in the US. The range of CV diseases exacerbated by cigarette smoke includes diabetic and obesity-related vascular diseases, stroke, myocardial infarction, peripheral vascular, and renal disease (20,35,50). Heart attacks are three times more common in smokers than in nonsmokers, and it is estimated that ϳ30% of deaths from coronary heart disease in the US are attributable to smoking (35). We and others (16,18) have demonstrated the importance of chemically stable compounds present in the gas phase of cigarette smoke in mediating endothelial injury and a...

A systematic review of possible serious adverse health effects of nicotine replacement therapy

“…In contrast, the short-term (≤12 weeks) administration of nicotine to animals has been shown to enhance or aggravate existing cardiovascular disease (i.e. chronic hypertension, atherosclerosis, myocardial ischaemia/reperfusion injury) in experimental models (Bui et al 1995; Lau et al 2006; Sridharan et al 1985; Zhou et al 2013). The results of these non-clinical studies suggest the potential for serious cardiovascular adverse effects with nicotine exposure and support the need for a comprehensive review of studies investigating the presence of such SAHE in NRT users.…”

Crosstalk Between Co-cultured A549 Cells and THP1 Cells Exposed to Cigarette Smoke

“…A major role in CS cytotoxicity in A549 cells may be played by acrolein and hydrogen peroxide (Aoshiba and Nagai 2003). Monocytes are more resistant to oxidative stress, but activation of THP1 cells by CS may be mediated by nicotine, which is able to activate immune cells (Zhou et al 2013). It has been shown that antioxidants prevent CS toxicity in A549 cells (Banerjee et al 2008) and decrease protein damage, inflammation, apoptosis, and lung injury in smoke-exposed animals (Rahman 2012), supporting the major role of oxidative stress in CS-induced cytotoxicity.…”

Signaling network of lipids as a comprehensive scaffold for omics data integration in sputum of COPD patients

“…4-HNE is a highly reactive and diffusible by-product, which can induce apoptosis, inflammation, emphysema and enlargement of airspaces in COPD [48,49]. Furthermore, oxidation of LDL is also a major risk factor for atherosclerosis and cardiovascular disease [50]. MDA is a carcinogenic product of lipid peroxidation reactions which is found to increase in the sputum of COPD patients (Fig.…”