Impaired transcriptional response of the murine heart to cigarette smoke in the setting of high fat diet and obesity.
Impaired transcriptional response of the murine heart to cigarette smoke in the setting of high fat diet and obesity.
复制标题
在高脂肪饮食和肥胖的情况下，小鼠心脏对香烟烟雾的转录反应受损。
DOI：
10.1021/tx400078b
复制
发表时间：
2013
影响因子：
4.1
通讯作者：
Bigelow,DianaJ
中科院分区：
文献类型：
--
作者：
Tilton,SusanC;Karin,NormanJ;Webb-Robertson,Bobbie-JoM;Waters,KatrinaM;Mikheev,Vladimir;Lee,KMonica;Corley,RichardA;Pounds,JoelG;Bigelow,DianaJ
吸烟和肥胖都是心血管心脏病的公认危险因素，它们共同导致疾病发病更早和更严重。为了确定肥胖背景下心脏对香烟烟雾暴露反应的早期信号事件，我们将正常体重和高脂肪饮食诱导的肥胖（DIO） C57BL/6小鼠暴露于两周内反复吸入主流（MS）或侧流（SS）香烟烟雾中，监测心脏和肺转录组的影响。MS烟雾（250 μg湿总颗粒物(WTPM)/L， 5 h/天）暴露在正常体重动物的肺中，1466个差异表达的肺基因（p< 0.01）引起了强烈的细胞和分子炎症反应，而在相同动物的心脏中，反应（463个基因）大大减弱。相比之下，暴露于CO浓度与MS烟雾（~ 250 CO ppm）相当的SS烟雾（85 μg WTPM/L）诱导了弱的肺反应（328个基因），但广泛的心脏反应（1590个基因）。SS烟雾和在较小程度上MS烟雾优先引发缺氧和应激反应基因，以及预测血管平滑肌和内皮早期变化的基因，心血管疾病的前兆。吸烟暴露后，正常体重小鼠最敏感的吸烟诱导的心脏转录变化在DIO小鼠中基本不存在，而与脂肪酸利用有关的基因则不受影响。同时，烟雾暴露抑制了DIO小鼠心脏中诱导的多种蛋白质组维持基因。总之，这些结果强调了心脏对SS烟雾的敏感性，并揭示了健康个体在高脂肪饮食和肥胖环境中缺乏的适应性反应。
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, 5 h/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 much-attenuated response (463 genes) in the hearts of the same animals. In contrast, exposures to SS smoke (85 μg WTPM/L) with a CO concentration equivalent to 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.