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

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.