Down‐Regulation of α₁‐Adrenoceptor Expression by Lipid‐Soluble Smoke Particles through Transcriptional Factor Nuclear Factor‐κB Pathway

Abstract

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 α -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 µ l/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 α 1A -adrenoceptor mRNA expression in the smooth muscle, while α 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-κ B (NF-κ B) pathway inhibitor, markedly reversed the DSP-induced down-regulation of α 1A -adrenoceptor expression in the smooth muscle at both functional and mRNA levels. Thus, we have demonstrated that smoking-induced down-regulation of α 1A -adrenoceptor expression was via the transcriptional factor NF-κ B pathway.Epidemiological studies have shown that there are strong links between cardiovascular disease and cigarette smoking, including secondhand smoking [1]. Smoking per se has been reported to result in 5 million premature deaths per year worldwide, and the majority of these are due to cardiovascular events [2]. Smoking is believed to cause damage to arterial wall with dysfunction of the endothelium and smooth muscle cells, and subsequently enhance atherosclerotic plaque formation [3]. However, the molecular mechanisms behind this process are still largely unknown.Previous studies showed that lipid-soluble smoke particles (DSP) cause damage to vascular endothelial cells (VEC) and vascular smooth muscle cells (VSMC) [4]; reduce the release of pro-stacyclin from VEC [5,6], and increase 125 I-low density lipoprotein (LDL) uptake by VSMC. In addition, we have recently demonstrated that DSP reduced endotheliumdependent dilatation in rat mesenteric arteries and human middle cerebral arteries [7], and resulted in up-regulation of endothelin type A and B (ET A and ET B ) receptors in the smooth muscle of rat mesenteric arteries [8] and rat bronchi [9].Adrenoceptor belongs to G-protein-coupled receptors (GPCRs) family. In the vasculature, adrenoceptor, particularly α -adrenoceptor, has been demonstrated to play important roles in regulating blood flow and blood pressure by altering artery resistance in cardiovascular disease [10]. Experimental and clinical studies showed that there is an increased α -adrenoceptor-mediated vasoconstriction in hypertensive patien...

The Role of NF‐κB1A Promoter Polymorphisms on Coronary Artery Disease Risk

“…found that this study is the first to demonstrate that lipid‐soluable smoke particles inhibit the contractile response of arteries in rat and human beings to down‐regulate the expression of G‐protein coupled family in vascular smooth muscle cells. This down‐regulation occurs via transcription and requires activation of intracellular NF‐κB signal pathway, which is an important inflammatory signalling .…”

Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro

“…Besides the ETB2 receptor, the alteration of G-protein coupled receptors (GPCRs) like thromboxane A2 receptors and α1A-adrenoceptors (Zhang et al, 2007) in the VSMC has been studied under pathophysiological conditions. These findings along with additional clinical and experimental data provided the importance of the alteration of GPCRs in the pathogenesis of atherosclerotic CVDs, for their capabilities in regulating vascular tone and VSMC proliferation, which result in structure changes in the vascular wall associated with adverse remodeling, plaque formation, and in clinical sequelae such as myocardial infarction, stroke, and ischemia.…”

Exposure to ambient particulate matter induces oxidative stress in lung and aorta in a size- and time-dependent manner in rats

“…5,26,27 OxS has been implicated in the etiology of several diseases linked to exposure to environmental toxicants, including PM, due to the increment of ROS concentrations that exceed antioxidant defenses and oxidase macromolecules. [30][31][32][33] Protein carbonylation is an irreversible, nonenzymatic process that results in the introduction of carbonyl groups into the protein molecule, leading to changes in its conformation. Protein carbonylation has been associated with the development of cardiovascular and respiratory diseases 34,35 and has been used as a biomarker of oxidized proteins.…”