Upregulation of AT1 receptor gene on activation of protein kinase Cbeta/nicotinamide adenine dinucleotide diphosphate oxidase/ERK1/2/c-fos signaling cascade mediates long-term pressor effect of angiotensin II in rostral ventrolateral medulla.
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 (AT1R) 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 AT1R-dependent long-term pressor effects of angiotensin II via transcriptional induction of the proto-oncogene c-fos gene in RVLM.


RESULTS
In Sprague-Dawley rats, a microinjection of angiotensin II bilaterally into the RVLM induced membrane-bound translocation of the conventional PKCalpha, PKCbeta or PKCgamma isoform, phosphorylation of the p47 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 phosphorylation, and an antisense oligonucleotide (ASON) complementary to PKCbeta 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 AT1R expression in the ventrolateral medulla induced by intracerebroventricular infusion of angiotensin II.


CONCLUSIONS
We concluded that the PKCbeta/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.
Chan
Samuel H H
SH
Center for Neuroscience, National Sun Yat-sen University, and Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China.
Wang
Ling-Lin
LL
Tseng
Huey-Ling
HL
Chan
Julie Y H
JY
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
D017931:DNA Primers; D016760:Proto-Oncogene Proteins c-fos; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3