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(Hypertension. 1997;29:414.)
© 1997 American Heart Association, Inc.

State-of-the-Art-Lecture

Expression of Guanylyl Cyclase-A/Atrial Natriuretic Peptide Receptor Blocks the Activation of Protein Kinase C in Vascular Smooth Muscle Cells

Role of cGMP and cGMP-Dependent Protein Kinase

Ravindra Kumar; Willie A. Cartledge; Thomas M. Lincoln; Kailash N. Pandey

From the Department of Biochemistry and Molecular Biology (R.K., W.A.C., K.N.P.), Medical College of Georgia, School of Medicine, Augusta, and the Department of Pathology (T.M.L.), University of Alabama at Birmingham.

Correspondence to Dr Kailash N. Pandey, Department of Biochemistry and Molecular Biology, Medical College of Georgia School of Medicine, Augusta, GA 30912-2100

To understand the molecular mechanisms of cellular signaling of atrial natriuretic peptide (ANP), we have studied its effect on the enzymatic activity of endogenous and overexpressed protein kinase C (PKC) in rat thoracic aortic vascular smooth muscle (RTASM) cells. Angiotensin II (ANG II), endothelin-1 (ET-1), and 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated fourfold to fivefold PKC activity in PKC-cDNA-transfected RTASM cells. However, pretreatment of these cells with ANP significantly inhibited the agonist-stimulated PKC activity in a dose-dependent manner. The inhibitory effect of ANP was more effective if cells were transfected with both PKC- and guanylyl cyclase-A/atrial natriuretic peptide receptor (Npra) cDNAs. The agonist-stimulated PKC activity was also inhibited if RTASM cells were pretreated with cGMP analog 8-bromo-cGMP; however, the treatment of cells with a cAMP analog, dibutyryl-cAMP, did not show any discernible effect. The pretreatment of cells with Npra antagonist A-71915, significantly blocked the production of cGMP as well as the inhibitory effect of ANP on PKC activity. To further examine whether the antagonistic action of ANP and 8-bromo-cGMP on agonist-stimulated PKC activity were mediated through cGMP-dependent protein kinase (PKG), cells were treated with ANP or 8-bromo-cGMP and activators of PKC in the presence of KT-5823, a specific inhibitor of PKG. The treatment of cells with KT-5823 significantly attenuated the inhibitory effects of both ANP and 8-bromo-cGMP on agonist-stimulated PKC activity. The results from these studies provide strong evidence that ANP antagonizes the activation of PKC in RTASM cells, involving guanylyl cyclase-A receptor Npra and second messenger cGMP. Our data further support the notion that ANP acts as a negative mediator of signaling cross-talks between Npra and PKC in a cGMP-dependent manner, probably involving cGMP-dependent protein kinase in this process.

Key Words: atrial natriuretic peptide • guanylyl cyclase • receptor-A • protein kinase C • cGMP • angiotensin II • phorbol ester • vascular smooth muscle cells

Abbreviations: ANG II = angiotensin II • ANP = atrial natriuretic peptide • BNP = brain natriuretic peptide • CNP = C-type natriuretic peptide • ET-1 = endothelin-1 • IP₃ = inositol 1,4,5 triphosphate • Npra = guanylyl cyclase-linked ANP receptor • PKC, PKG = protein kinase C, G • RTASM = rat thoracic aortic smooth muscle • TPA = 12-O-tetradecanolyphorbol 13-acetate

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