Abstract 14523: Attenuating ErbB2 Signaling in the Rostral Ventrolateral Medulla Reduces Nitric Oxide Synthesis and Induces Hypertension
Background: Neuregulin-1 (NRG-1), a member of the epidermal growth factor family, is involved in cell-cell communication. We previously reported that activation of NRG-1/ErbB signaling in the rostral ventrolateral medulla (RVLM, a cardiovascular center in the brainstem) lowered arterial pressure (AP) via sympathoinhibition. Furthermore, we found reduced ErbB2 expression in the brainstem of hypertensive rats suggesting the possible involvement of NRG-1/ErbB signaling in neural mechanism(s) of hypertension. Nitric oxide (NO) in the RVLM is also known to inhibit the central sympathetic outflow by augmenting γ-aminobutyric acid (GABA) action in the RVLM. Although it has been reported that NRG-1 interacts with NO, it is unknown whether the NRG-1/ErbB signaling in the RVLM influences NO with GABA action.
Hypothesis: Inhibition of ErbB2 in the RVLM increases AP via attenuating the GABA action through the reduction of NO synthesis.
Methods and Results: We administered small interference RNA (siRNA) for ErbB2 into the RVLM of Wistar-Kyoto (WKY) rats to inhibit local ErbB2 expression. Inhibition of ErbB2 increased mean AP (ΔMAP: 23.2±9.3mmHg, telemetry), heart rate (ΔHR: 42.2±10.0 bpm) and urinary excretion of norepinephrine (uNE, a marker of sympathoexcitation) at day 1 to 5 after treatment. Time course of ErbB2 expression inhibition in the RVLM was consistent with changes in MAP and HR. Furthermore, inhibition of ErbB2 also reduced expression levels of neural NO synthase and endothelial NO synthase in the RVLM (n=5, p<0.05). In anesthetized WKY rats, prior microinjection of a NOS inhibitor (L-NMMA: 50 pmol) or a GABA-A receptor antagonist (bicuculline, 100 pmol) into the RVLM attenuated the NRG-1 (2.5 pmol)-induced depressor response (L-NMMA: -22.9±2.9 vs. -7.1±1.2 mmHg, n=5, p<0.05, bicuculline: -22.9±2.9 vs. -4.3±2.5 mmHg, n=5, p<0.05).
Conclusion: Inhibition of ErbB2 expression in the RVLM causes hypertension at least in part by reducing NO synthesis associated with inhibiting GABA action. NRG-1/ErbB signaling would be in the upstream of the NO synthesis.
- © 2011 by American Heart Association, Inc.