PMID- 20814019 OWN - NLM STAT- MEDLINE DCOM- 20101122 LR - 20210208 IS - 1524-4571 (Electronic) IS - 0009-7330 (Linking) VI - 107 IP - 9 DP - 2010 Oct 29 TI - Transcriptional upregulation of brain-derived neurotrophic factor in rostral ventrolateral medulla by angiotensin II: significance in superoxide homeostasis and neural regulation of arterial pressure. PG - 1127-39 LID - 10.1161/CIRCRESAHA.110.225573 [doi] AB - RATIONALE: Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of neurogenic vasomotor tone are located, contributes to neural mechanisms of hypertension. Emerging evidence suggests that brain-derived neurotrophic factor (BDNF) manifests "nontrophic" actions. OBJECTIVE: We assessed the hypothesis that BDNF plays an active role in oxidative stress-associated neurogenic hypertension by maintaining superoxide anion (O(-)(.)(2)) homeostasis in RVLM. METHODS AND RESULTS: In Wistar-Kyoto rats, microinjection of angiotensin II (Ang II) bilaterally into RVLM upregulated BDNF mRNA and protein and induced cAMP response element binding protein (CREB) phosphorylation. The Ang II-induced BDNF upregulation in RVLM was attenuated by coadministration of the NADPH oxidase inhibitor apocynin; the superoxide dismutase mimetic tempol; or an antisense oligonucleotide against CREB. Intracisternal infusion of Ang II elicited phosphorylation of p47(phox) subunit of NADPH oxidase, suppression of mitochondrial electron coupling capacity, and augmentation in mitochondrial uncoupling protein (UCP)2 expression in RVLM. The former 2 cellular events were enhanced, whereas UCP2 upregulation was attenuated by gene knockdown of BDNF or depletion of tropomyosin receptor kinase (Trk)B ligands with recombinant human TrkB-Fc fusion protein. The same treatments also significantly potentiated both Ang II-induced (O(-)(.)(2)) production in RVLM and chronic pressor response. CONCLUSIONS: Ang II induces (O(-)(.)(2)) -dependent upregulation of BDNF in RVLM via phosphorylation of CREB. The Ang II-activated BDNF/TrkB signaling, in turn, exerts negative-feedback regulation on tissue (O(-)(.)(2)) level in RVLM through inhibition of p47(phox) phosphorylation, preservation of mitochondrial electron transport capacity, and upregulation of mitochondrial UCP2, resulting in protection against Ang II-induced oxidative stress and long-term pressor response. FAU - Chan, Samuel H H AU - Chan SH AD - Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Taiwan 813, Republic of China. FAU - Wu, Chih-Wei J AU - Wu CW FAU - Chang, Alice Y W AU - Chang AY FAU - Hsu, Kuei-Sen AU - Hsu KS FAU - Chan, Julie Y H AU - Chan JY LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100902 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 11062-77-4 (Superoxides) RN - 11128-99-7 (Angiotensin II) SB - IM MH - Angiotensin II/*physiology MH - Animals MH - Blood Pressure/*physiology MH - Brain-Derived Neurotrophic Factor/*biosynthesis MH - Homeostasis/physiology MH - Humans MH - Male MH - Medulla Oblongata/*metabolism MH - Neurons/metabolism MH - Rats MH - Rats, Inbred SHR MH - Rats, Inbred WKY MH - Signal Transduction/physiology MH - Superoxides/*metabolism MH - Transcriptional Activation/physiology MH - Up-Regulation/*physiology EDAT- 2010/09/04 06:00 MHDA- 2010/12/14 06:00 CRDT- 2010/09/04 06:00 PHST- 2010/09/04 06:00 [entrez] PHST- 2010/09/04 06:00 [pubmed] PHST- 2010/12/14 06:00 [medline] AID - CIRCRESAHA.110.225573 [pii] AID - 10.1161/CIRCRESAHA.110.225573 [doi] PST - ppublish SO - Circ Res. 2010 Oct 29;107(9):1127-39. doi: 10.1161/CIRCRESAHA.110.225573. Epub 2010 Sep 2.