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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.108.047993v1 74/4/1000    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by García-Cazarín, M. L. Articles by Piascik, M. T. PubMed PubMed Citation Articles by García-Cazarín, M. L. Articles by Piascik, M. T.

The _1D-Adrenergic Receptor Induces Vascular Smooth Muscle Apoptosis via a p53-Dependent Mechanism

Departments of Molecular and Biomedical Pharmacology (M.L.G.-C., J.L.S., M.T.P.) and Toxicology (D.K.St.C.), University of Kentucky, Lexington, Kentucky

Activation of the endogenous ₁-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 ₁-AR resulted in smooth muscle cell apoptosis. Both the increase in ROS and apoptotic cell death were blocked by the nonselective ₁-AR antagonist prazosin as well as the selective _1D-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 ₁-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-, an inhibitor of the tumor suppressor protein p53, had no effect on ROS generation but did block _1D-AR-induced apoptosis. Activation of the _1D-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-. Apoptosis was also blocked by small interfering RNA directed against p53. These data show that the _1D-AR is coupled to the generation of mitochondrial ROS by a pathway involving p38 and NADPH oxidase. Sustained activation of the _1D-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 _1D-AR and p53.

Address correspondence to: Dr. Michael T. Piascik, Department of Molecular and Biomedical Pharmacology, The University of Kentucky College of Medicine, 800 Rose St., UKMC MS 305, Lexington, KY 40536-0084. E-mail: mtp{at}uky.edu