alpha(1D)-adrenergic receptors and mitogen-activated protein kinase mediate increased protein synthesis by arterial smooth muscle

被引:98
作者
Xin, XH [1 ]
Yang, NY [1 ]
Eckhart, AD [1 ]
Faber, JE [1 ]
机构
[1] UNIV N CAROLINA,DEPT PHYSIOL,CHAPEL HILL,NC 27599
关键词
D O I
10.1124/mol.51.5.764
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Catecholamines may influence vascular smooth muscle cell (SMC) growth and vascular hypertrophic diseases. We previously demonstrated that stimulation of alpha(1)-adrenoceptors (AR) causes hypertrophy of vascular SMCs in vitro and in situ. Here, we used adult rat aorta SMCs that express alpha(1D)- and alpha(1B)-ARs (but not alpha(1A)-ARs) in vitro to examine the mechanisms and alpha(1)-AR subtypes involved. Norepinephrine (NE) increased protein synthesis and content in a time- and dose-dependent manner. To identify the responsible alpha(1)-AR subtype, we first documented the selectivity of two alpha(1)-AR subtype antagonists, BMY 7378 (alpha(1D)-AR antagonist) and chloroethylclonidine (CEC; alpha(1B)-AR antagonist), using Rat-1 fibroblasts stably transfected with the three different rodent alpha(1)-AR cDNAs. NE dose-dependently increased protein synthesis in each cell line. In alpha(1D) fibroblasts, BMY 7378 inhibited growth and protected (alpha(1)-ARs from CEC alkylation while having little blocking or protecting effect on the growth induced by stimulation of fibroblasts that express alpha(1A) - or alpha(1B)-ARs. In rat aorta SMCs, pretreatment with CEC in the presence of BMY 7378 to protect alpha(1D)-ARs had no effect on NE-induced protein synthesis. BMY 7378 inhibited the SMC growth response with a pK(b) of 8.4. NE caused rapid and transient p42-p44 mitogen-activated protein kinase (MAPK) activation that was alpha(1D)-AR dependent. Furthermore, NE caused tyrosine phosphorylation of multiple cellular proteins, phosphorylation of Raf-1, and stimulation of c-fos mRNA expression in aorta SMCs. The selective MAPK kinase inhibitor PD 98059 inhibited NE-induced protein synthesis and MAPK activation with IC50 values of 2.3 and 1.6 mu M, respectively. These data demonstrate that SMC growth induced by NE is mediated by alpha(1D)-ARs that couple to activation of the MAPK cascade.
引用
收藏
页码:764 / 775
页数:12
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