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p22phox inhibition in Skeletal Muscle Normalizes the Exaggerated Exercise Pressor Reflex in Chronic Heart Failure
Author(s) -
Wang Hanjun,
Gao Lie,
Zimmerman Matthew C.,
Zucker Irving H.,
Wang Wei
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.619.1
Subject(s) - medicine , nadph oxidase , endocrinology , skeletal muscle , hindlimb , stimulation , heart failure , chemistry , in vivo , biology , oxidative stress , microbiology and biotechnology
In chronic heart failure (CHF), an overactive skeletal muscle exercise pressor reflex (EPR) results in excessive sympatho‐excitation and exercise intolerance. However, the mechanism(s) of the exaggerated EPR in CHF state remains to be determined. We recently found that muscle NADPH oxidase‐derived reactive oxygen species (ROS) plays an excitatory role in modulation of EPR function in normal rats. In this study, we used the technique of in vivo siRNA to selectively knockdown the protein expression of p22 phox (a NADPH oxidase subunit) in hindlimb muscles of CHF rats in order to investigate the contribution of NADPH oxidase‐derived ROS to the exaggerated EPR in CHF. Data from western blotting and immunofluorescence experiments showed that compared with sham rats, the protein expression of p22 phox in triceps surae muscle was significantly increased in CHF rats (ratio of p22 phox to GAPDH: 0.32±0.03 vs. 0.15±0.02, CHF vs. Sham, n=5, P<0.05). Silencing p22 phox in skeletal muscle with in vivo siRNA (1 week) dramatically decreased the protein expression by almost 70% in CHF rats. Animal experiments showed that gene silencing of p22 phox in hindlimb muscles significantly attenuated the EPR‐evoked pressor response to a 30‐s static contraction induced by electrical stimulation of L4/L5 ventral roots in CHF rats (+33.1±2.8 vs. +20.8±1.5 mmHg, CHF vs. CHF+siRNA, n=5, P<0.05) whereas treatment with control siRNA has no effect on the EPR function. These data suggest that elevated muscle NADPH oxidase‐derived ROS contributes to the exaggerated EPR in the CHF state.