CORTICOSTERONE AND 11-DEHYDROCORTICOSTERONE STIMULATE NA,K-ATPASE GENE-EXPRESSION IN VASCULAR SMOOTH-MUSCLE CELLS

Background. In mineralocorticoid target tissues such as kidney and col on, the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD) cat alizes the reversible conversion of corticosterone (CS) to inactive 11 -dehydrocorticosterone (DHCS) in rats, and cortisol to inactive cortis one in humans. This enzyme is also expressed in vascular smooth muscle cells (VSMC). Methods. In cultured VSMC from rat thoracic aortae, we examined the effects of CS and DHCS on Na,K-ATPase (alpha 1- and beta 1-mRNA accumulation by Northern blot analysis, on alpha 1- and beta 1- subunit protein accumulation by Western blot analysis, and on Na,K-ATP ase activity by the coupled assay method. Results. In VSMC, CS and DHC S (10(-6) M) increased alpha 1-mRNA level 2.6- and 2.5-fold at 48 hour s and beta 1-mRNA level 9.2- and 9.1-fold at 12 hours, respectively. T he RNA transcription inhibitor (actinomycin D) abolished both CS- and DHCS-mediated alpha 1- and beta 1-mRNA induction. The glucocorticoid r eceptor antagonist (RU38486) and the mineralocorticoid receptor antago nists (ZK91587) inhibited both CS- and DHCS-mediated alpha 1- and beta 1-mRNA induction. The 11 beta OHSD inhibitor (carbenoxolone) inhibite d DHCS-mediated alpha 1- and beta 1-mRNA induction, whereas it caused no effect on CS-mediated alpha 1- or beta 1-mRNA induction. The additi on of CS or DHCS to VSMC significantly increased alpha 1- and beta 1-s ubunit protein levels and Na,K-ATPase activity. When adrenalectomized rats were treated with CS or DHCS for 12 hours, aorta alpha 1- and bet a 1-mRNA levels increased 3.0- and 8.7-fold or 3.4- and 8.4-fold, resp ectively. Conclusions. In VSMC, both CS and DHCS stimulate Na,K-ATPase alpha 1- and beta 1-mRNA accumulation, alpha 1- and beta 1-subunit pr otein accumulation, and Na,K-ATPase activity. The CS-mediated alpha 1- and beta 1-mRNA induction occurs independently of 11 beta OHSD, where as the DHCS-mediated alpha 1- and beta 1-mRNA induction occurs through 11 beta OHSD-dependent mechanisms, possibly via conversion of inactiv e DHCS into active CS.