Lipid-soluble Cigarette Smoke Particles Induced Vascular Endothelin Type A Receptor Up-Regulation through Activation of ERK1/2 Signal Pathways.

Abnormal contraction of vessels termed 'vasospasm' is associated with various cardiovascular diseases. Smoking is a well-known risk factor that increases vasospasm. However, the molecular mechanisms by which smoking leads to vasospasm and cardiovascular disease are not fully understood. This study was designed to examine whether DMSO-extracted cigarette smoke particles (DSP) could induce up-regulation of vascular endothelin type A (ET ) receptors, and whether ET receptor is up-regulated through activation of extracellular regulated protein kinases 1 and 2 (ERK1/2) signal pathways. Mesenteric arterial segments from rats were cultured in the presence of DSP, water-extracted cigarette smoke particles (WSP) or equivalent concentration of nicotine for up to 24 hr. The results showed that DSP, but not WSP or nicotine, induced ET receptor up-regulation with increased ET receptor-mediated contraction (myograph, p < 0.001). Simultaneously, the expression of ET receptor mRNA (real-time PCR, p < 0.001) and protein (immunohistochemistry) were enhanced in the smooth muscle cells, suggesting that the lipid-soluble substances contained in cigarette smoke were responsible for the effects of DSP. Actinomycin D (a general transcriptional inhibitor) decreased ET receptor mRNA expression and attenuated receptor-mediated contraction (p < 0.001), while DSP accelerated ET receptor mRNA degradation (p < 0.01) and promoted the translation of ET receptor mRNA into protein. Furthermore, the up-regulation of ET receptors was significantly attenuated by inhibition of ERK1/2 signal pathways (p < 0.001). In conclusion, DSP most likely activate ERK1/2 signal pathway-mediated transcriptional and post-transcriptional (translational) mechanisms that lead to vascular ET receptor up-regulation, which might contribute to vasospasm and the development of smoking-associated cardiovascular diseases.