Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Abstract

Smoking and obesity are each well-established risk factors for cardiovascular heart disease, which together impose earlier onset and greater severity of disease. To identify early signaling events in the response of the heart to cigarette smoke exposure within the setting of obesity, we exposed normal weight and high fat diet-induced obese (DIO) C57BL/6 mice to repeated inhaled doses of mainstream (MS) or sidestream (SS) cigarette smoke administered over a two week period, monitoring effects on both cardiac and pulmonary transcriptomes. MS smoke (250 µg wet total particulate matter (WTPM)/L, 5h/day) exposures elicited robust cellular and molecular inflammatory responses in the lung with 1466 differentially expressed pulmonary genes (p<0.01) in normal weight animals, and a muchattenuated response (463 genes) in the hearts of the same animals. In contrast, exposures to SS smoke (85 µg WTPM/L) with an equivalent CO concentration as that of MS smoke (~250 CO ppm), induced a weak pulmonary response (328 genes), but an extensive cardiac response (1590 genes). SS smoke, and to a lesser extent MS smoke preferentially elicited hypoxia- and stress-responsive genes as well as genes predicting early changes of vascular smooth muscle and endothelium, precursors of cardiovascular disease. The most sensitive smoke-induced cardiac transcriptional changes of normal weight mice were largely absent in DIO mice after smoke exposure, while genes involved in fatty acid utilization were unaffected. At the same time, smoke exposure suppressed multiple proteome maintenance genes induced in the hearts of DIO mice. Together these results underscore the sensitivity of the heart to SS smoke and reveal adaptive responses in healthy individuals that are absent in the setting of high fat diet and obesity.

Modelling the Impact of Chronic Cigarette Smoke Exposure in Obese Mice: Metabolic, Pulmonary, Intestinal, and Cardiac Issues

“…Here, we confirmed that obesity or CS independently induce marked heart hypertrophic remodeling. These results are in accordance with a transcriptomic study described by Tilton et al, revealing an extensive cardiac response to CS in lean mice, in striking contrast with obese mice [67]. Interestingly, we also observed that obesity, as already shown by Wang et al [68], as well CS exposure significantly increased cardiac fibrosis characterized by Tgfb mRNA expression but only in lean mice.…”

Carbon black nanoparticles induce biphasic gene expression changes associated with inflammatory responses in the lungs of C57BL/6 mice following a single intratracheal instillation

“…Tissue injury following Table 5 Genes differentially expressed in response to CBNP exposure that were similarly altered in response to cigarette smoke or viral exposure. a References related to cigarette smoke (Thomson et al, 2013;Tilton et al, 2013) and virus response studies (Josset et al, 2012).…”

Metabolite Signatures in Hydrophilic Extracts of Mouse Lungs Exposed to Cigarette Smoke Revealed by 1H NMR Metabolomics Investigation

“…ATP, ADP, AMP and elevation of inosine in mice with both regular body weight and obese body weight in this study clearly pointed out that adenosine signaling pathway was profoundly perturbed by cigarette smoke exposure. Adenosine derivatives play many important biological roles in addition to being components of DNA and RNA [ 43 ]. For example, it has been proposed that adenosine derivatives accumulate through adenosine signaling in recruiting neutrophils in lungs, and are then detoxified by adenosine deaminases to inosine derivatives, which exert anti-inflammatory effects [ 44 - 47 ].…”