Down-regulation of alpha-adrenoceptor expression by lipid-soluble smoke particles through transcriptional factor...

Smoking is a strong risk factor for cardiovascular disease that is a leading cause of death and disability in Western countries. The present study was designed to investigate the effect of lipid-soluble smoke particles (DSP) on alpha-adrenoceptor expression in organ culture of rat mesenteric arteries and human epiploon arteries. Myograph and real-time reverse transcription-polymerase chain reaction were employed to assess vascular smooth muscle contractibility and the receptor mRNA expression in the smooth muscle cells. Organ culture of the arterial segments in the presence of DSP (0.2 microl/ml) resulted in a significantly decreased contractile response to norepinephrine, compared to control (i.e. in the presence of dimethyl sulfoxide) (P < 0.05). This was in parallel with a down-regulation of alpha(1A)-adrenoceptor mRNA expression in the smooth muscle, while alpha(2)-adrenoceptor mRNA expression remained unchanged. General transcription inhibitor actinomycin D (10(-5.4 )M), but not the translational inhibitor cycloheximide (10(-5 )M), significantly abolished the DSP-induced depressed contraction to norepinephrine. IMD-0354 (10(-7.5 )M), a specific nuclear factor-kappaB (NF-kappaB) pathway inhibitor, markedly reversed the DSP-induced down-regulation of alpha(1A)-adrenoceptor expression in the smooth muscle at both functional and mRNA levels. Thus, we have demonstrated that smoking-induced down-regulation of alpha(1A)-adrenoceptor expression was via the transcriptional factor NF-kappaB pathway.