Protein kinase C modulation of cyclic GMP in rat neonatal pulmonary vascular smooth muscle.
Protein kinase C (PKC) has been implicated in the control of vascular tone and mitogenesis in the adult pulmonary vasculature, but little is known about the role of PKC in the neonatal pulmonary vasculature. In addition, the vasodilator nitric oxide (NO) is important in the transition of the pulmonary circulation from fetal to postnatal life, and it is thought that attenuated production of NO and therefore, cGMP may contribute to the pathophysiology of a variety of forms of neonatal pulmonary vascular disease states. Although evidence exists for an interaction between PKC and NO in the adult pulmonary vasculature, the identification of specific roles for PKC in neonatal pulmonary vascular smooth muscle (NPVSM) has not been determined, and no studies have been done on the modulation of cGMP by PKC in NPVSM. Accordingly, immunoblot analysis revealed the expression of the alpha, delta, epsilon, and iota PKC isozymes in NPVSM. Treatment of NPVSM with 10 nM 4-beta phorbol myristate acetate (PMA), a PKC activator, induced translocation of PKCalpha, and PKCdelta from the soluble to the particulate fraction, while exposure to 10 nM endothelin-1 (ET-1), a potent vasoconstrictor and mitogenic substance, caused translocation of PKCdelta and PKCiota from the soluble to the particulate fraction. Sodium nitroprusside (SNP) significantly increased intracellular cGMP levels, an effect attenuated by PMA but not by ET-1. In addition, pretreatment with the specific PKC isozyme antagonist Go 6983 blocked the effect of PMA on cGMP levels. Collectively, these data demonstrate the expression and activation of multiple PKC isozymes in NPVSM, and indicate that PKC inhibits SNP-stimulated cGMP production in NPVSM. These data also suggest that complex intracellular signaling pathways by specific PKC isozymes may be important in the development of neonatal pulmonary vascular function.
Johnson
J A
JA
Department of Pharmacology and Toxicology, School of Medicine, The Program in Synapses and Cell Signaling, Institute of Molecular Medicine, Medical College of Georgia, Augusta, Georgia 30912, USA.
Barman
S A
SA
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis*; D019332:Endothelin-1 / Q000494:pharmacology; D015151:Immunoblotting; D007211:Indoles; D007527:Isoenzymes / Q000378:metabolism*; D008168:Lung / Q000502:physiology*; D008301:Maleimides; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D002227:Carbazoles; D019332:Endothelin-1; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D011493:Protein Kinase C; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate