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Brain p44/42 mitogen‐activated protein kinase contributes to the sympathetic response to blood‐borne TNF‐α in rats
Author(s) -
Zhang Zhihua,
Yu Yang,
Wei ShunGuang,
Felder Robert B.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1050.4
Subject(s) - mapk/erk pathway , tumor necrosis factor alpha , endocrinology , medicine , protein kinase a , small interfering rna , sympathetic nervous system , excitatory postsynaptic potential , western blot , signal transduction , kinase , proinflammatory cytokine , blood pressure , pharmacology , inflammation , biology , receptor , microbiology and biotechnology , rna , biochemistry , gene
Blood‐borne pro‐inflammatory cytokines act upon the central nervous system to increase sympathetic drive in normal and pathophysiological conditions including heart failure. The underlying signaling pathways are still poor understood. We tested the hypothesis that brain p44/42 mitogen‐activated protein kinase (MAPK) mediates tissue necrosis factor ‐ alpha (TNF‐α) induced sympatho‐excitatory responses. In urethane‐anesthetized rats, a centrally directed intracarotid artery (ICA) injection of TNF‐α elicited significant (p<0.05) increases in renal sympathetic nerve activity (RSNA), mean blood pressure (MBP) and heart rate (HR), and in hypothalamic phosphorylated p44/42 MAPK expression (Western blot and immunofluorescence). Intracerebroventricular (ICV) pretreatment (4 days before) with small interfering RNA (siRNA) using SMART pool siRNA targeting p44/42 MAPK significantly reduced the increases in RSNA, MBP and HR induced by ICA TNF‐α, but pretreatment with vehicle or control siRNA had no effect. TNF‐α induced increases in RSNA, MBP and HR were similarly diminished by a continuous ICV infusion of the p44/42 MAPK inhibitor PD98059. These data suggest that blood‐borne TNF‐α activates the brain p44/42 MAPK pathway to elicit sympatho‐excitatory responses. Supported by a VA Merit Review Award and NIH RO1 HL073986.