Abstract
BackgroundCigarette smoking is a strong cardiovascular risk factor and endothelin (ET) receptors are related to coronary artery diseases. The present study established an in vivo secondhand smoke (SHS) exposure model and investigated the hypothesis that cigarette smoke induces ET receptor upregulation in rat coronary arteries and its possible underlying mechanisms.Methodology/Principal FindingsRats were exposed to SHS for 200 min daily for 8 weeks. The coronary arteries were isolated and examined. The vasoconstriction was studied by a sensitive myograph. The expression of mRNA and protein for receptors was examined by real-time PCR, Western blot and immunofluorescence. Compared to fresh air exposure, SHS increased contractile responses mediated by endothelin type A (ETA) and type B (ETB) receptors in coronary arteries. In parallel, the expression of mRNA and protein for ETA and ETB receptors of smoke exposed rats were higher than that of animals exposed to fresh air, suggesting that SHS upregulates ETA and ETB receptors in coronary arteries in vivo. Immunofluorescence staining showed that the enhanced receptor expression was localized to the smooth muscle cells of coronary arteries. The protein levels of phosphorylated (p)-Raf-1 and p-ERK1/2 in smoke exposed rats were significantly higher than in control rats, demonstrating that SHS induces the activation of the Raf/ERK/MAPK pathway. Treatment with Raf-1 inhibitor GW5074 suppressed SHS-induced enhanced contraction mediated by ETA receptors, and inhibited the elevated mRNA and protein levels of ETA and ETB receptors caused by SHS. The results of correlation and regression analysis showed that phosphorylation of Raf and ERK1/2 were independent determinants to affect protein expression of ETB and ETA receptors.Conclusions/SignificanceCigarette smoke upregulates ETB and ETA receptors in rat coronary artery, which is associated with the activation of the Raf/ERK/MAPK pathway.
Highlights
Cigarette smoking is considered one of the most powerful risk factors for the development of cardiovascular disease (CVD), such as coronary artery disease (CAD), ischemic and congestive heart failure [1]
It has been demonstrated that cigarette smoking is associated with vascular impairment which includes injury to the vascular endothelium, producing superoxide anions, reducing production and bioavailability of nitric oxide, increasing production and release of endothelin, causing endothelial dysfunction, atherosclerosis, which are all hallmarks of CAD [23]
The present study has for the first time demonstrated that secondhand smoke (SHS) in vivo induces ET receptor upregulation in rat coronary arteries, and this upregulation is involved in the activation of the Raf/ERK/mitogen-activated protein kinases (MAPKs) pathway
Summary
Cigarette smoking is considered one of the most powerful risk factors for the development of cardiovascular disease (CVD), such as coronary artery disease (CAD), ischemic and congestive heart failure [1]. Smoking is strongly associated with the pathogenesis of CAD which may be attributed to the promotion of atherosclerosis, the triggering of coronary thrombosis, coronary artery spasm and reduced capacity of the blood to deliver oxygen [3]. Cigarette smoking is an established risk factor for atherosclerosis, the actual mediator of CAD associated with smoking is unknown. Cigarette smoking is a strong cardiovascular risk factor and endothelin (ET) receptors are related to coronary artery diseases. The present study established an in vivo secondhand smoke (SHS) exposure model and investigated the hypothesis that cigarette smoke induces ET receptor upregulation in rat coronary arteries and its possible underlying mechanisms
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