The α1D-adrenergic receptor induces vascular smooth muscle apoptosis via a p53-dependent mechanism

Mary L. García-Cazarín, Jennifer L. Smith, Daret K. St. Clair, Michael T. Piascik

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 (>4 h) 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)-1/-/-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 NH 2-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 a1D-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.

Original languageEnglish
Pages (from-to)1000-1007
Number of pages8
JournalMolecular Pharmacology
Issue number4
StatePublished - Oct 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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