%0 Journal Article %A Mary L. García-Cazarín %A Jennifer L. Smith %A Daret K. St. Clair %A Michael T. Piascik %T The α1D-Adrenergic Receptor Induces Vascular Smooth Muscle Apoptosis via a p53-Dependent Mechanism %D 2008 %R 10.1124/mol.108.047993 %J Molecular Pharmacology %P 1000-1007 %V 74 %N 4 %X Activation of the endogenous α1-adrenergic receptor (AR) associated with human aortic smooth muscle cells resulted in a dose- and time-dependent increase in the levels of mitochondrial reactive oxygen species (ROS). ROS increases were apparent within 10 min and maximal after 45 min. Prolonged activation (>4h) of the α1-AR resulted in smooth muscle cell apoptosis. Both the increase in ROS and apoptotic cell death were blocked by the nonselective α1-AR antagonist prazosin as well as the selective α1D-AR antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7, 9-dione (BMY 7378). Increases in ROS and apoptosis produced by α1-AR activation were also blocked by the p38 mitogen-activated protein kinase inhibitor 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB 202190) and the NAPDH oxidase inhibitor apocynin. The extracellular signal-regulated kinase 1/2 inhibitor 2′-amino-3′-methoxyflavone (PD 98059) or the c-Jun NH2-terminal kinase inhibitor 1, 9-pyrazoloanthrone anthra(1, 9-cd)pyrazol-6(2H)-one (SP 600125) was without effect on increases in ROS levels or apoptosis. Pifithrin-α, an inhibitor of the tumor suppressor protein p53, had no effect on ROS generation but did block α1D-AR-induced apoptosis. Activation of the α1D-AR resulted in translocation of p53 to the mitochondria. The mitochondrial translocation of p53 was blocked by prazosin, BMY 7378, apocynin, SB 202190, and pifithrin-α. Apoptosis was also blocked by small interfering RNA directed against p53. These data show that the α1D-AR is coupled to the generation of mitochondrial ROS by a pathway involving p38 and NADPH oxidase. Sustained activation of the α1D-AR results in smooth muscle cell apoptosis in a pathway that involves the tumor suppressor protein p53 and the mitochondrial translocation of p53. The data also provide evidence of a linkage between the α1D-AR and p53. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/74/4/1000.full.pdf