Abstract
Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity
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The rats were fed either a high fat (HFD) or normal rat chow (NFD) diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP 146 ± 3 vs. 130 ± 5 mmHg in NFD , p<0.05), aortic superoxide (O
2
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1357 ± 142 vs. 847 ± 102 counts/min/mg in NFD, p<0.05) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR, Emax: 85 ± 5 vs. 99 ± 1% in NFD, p<0.05). Nicotine further increased SBP (159 ± 5 mmHg, p<0.05), O
2
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(1689 ± 87 counts/min/mg, p<0.05) and impaired eNOS and EDR (Emax: 72 ± 4%, p<0.05) in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2-4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet–induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.
