Journal
JOURNAL OF HYPERTENSION
Volume 25, Issue 9, Pages 1845-1861Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e328217b286
Keywords
angiotensin II; angiotensin subtype 1 receptor; c-fos gene; extracellular signal-regulated protein kinase 1/2; nicotinamide adenine dinucleotide diphosphate oxidase; protein kinase C; rostral ventrolateral medulla
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Objective Angiotensin II induces the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) 1/2 via the activation of nicotinamide adenine dinucleotide diphosphate (NADPH) oxidase on stimulation of the angiotensin subtype 1 receptor (AT, R) in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone and blood pressure are located. Angiotensin II-activated p38 MAPK in RVLM promotes a short-term pressor effect via augmented glutamatergic neurotransmission. We tested the hypothesis that the NADPH oxidase-dependent phosphorylation of ERK1/2 after the activation of conventional protein kinase C (PKC) mediates the AT, R-dependent long-term pressor effects of angiotensin 11 via transcriptional induction of the proto-oncogene c-fos gene in RVLM. Methods and results In Sprague-Dawley rats, a microinjection of angiotensin 11 bilaterally into the RVLM induced membrane-bound translocation of the conventional PKC alpha, PKC beta or PKC gamma isoform, phosphorylation of the p47(phox) subunit of NADPH oxidase and ERK1/2, followed by phosphorylation of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB), and c-fos induction. The PKC inhibitor antagonized angiotensin II-induced p47(phox) phosphorylation, and an antisense oligonucleotide (ASON) complementary to PKCP messenger RNA suppressed angiotensin II-induced ERK1/2 activation, phosphorylation or DNA binding activity of CREB, and upregulation of c-fos mRNA expression in the ventrolateral medulla. Furthermore, a microinjection of ERK1/2, CREB or c-fos ASON into the RVLM significantly reduced the long-term pressor effect and augmented AT, R expression in the ventrolateral medulla induced by intracerebroventricular infusion of angiotensin II. Conclusion We concluded that the PKC beta/NADPH oxidase/ERK1/2/CREB/c-fos cascade represents a novel signaling cascade that mediates the long-term pressor effect induced by angiotensin II in the RVLM.
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