title: Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension.
abstract: Blood-borne angiotensin II (ANG II) can upregulate p44/42 mitogen-activated protein kinase (MAPK) signaling and ANG II type-1 receptors in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center. We tested the hypothesis that brain p44/42 MAPK signaling contributes to the development of ANG II-induced hypertension. The ANG II infusion (120 ng/kg per min, subcutaneously) induced increases in phosphorylated p44/42 MAPK and ANG II type-1 receptors in the PVN after 1 week, before the onset of hypertension, that were sustained as hypertension developed during a 2- or 3-week infusion protocol. Bilateral PVN microinjections of small interfering RNAs for p44/42 MAPK, at the onset of the ANG II infusion or 1 week later, prevented the early increase in p44/42 MAPK activity. The early treatment normalized ANG II type-1 receptor expression in the PVN and attenuated the hypertensive response to the 2-week infusion of ANG II. The later small interfering RNA microinjections had a transient effect on ANG II type-1 receptor expression in PVN and no effect on the hypertensive response to the 3-week infusion of ANG II. The early treatment also normalized the pressure response to ganglionic blockade. The ANG II infusion induced increases in mRNA for proinflammatory cytokines that were not affected by either small interfering RNA treatment. These results suggest that the full expression of ANG II-induced hypertension depends on p44/42 MAPK-mediated effects. A potential role for p44/42 MAPK in modulating the ANG II-induced central inflammatory response might also be considered. MAPK signaling in PVN may be a novel target for early intervention in the progression of ANG II-dependent hypertension.
authors: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors: Yang
authors: Y
authors: Yu
authors: Bao-Jian
authors: BJ
authors: Xue
authors: Zhi-Hua
authors: ZH
authors: Zhang
authors: Shun-Guang
authors: SG
authors: Wei
authors: Terry G
authors: TG
authors: Beltz
authors: Fang
authors: F
authors: Guo
authors: Alan Kim
authors: AK
authors: Johnson
authors: Robert B
authors: RB
authors: Felder
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3