[2006] [P2914] Long-term
electric Vagus nerve stimulation activates the Neuregulin-1
cardioprotective pathway in left ventricular myocardium of dogs with heart
failure
R.C. Gupta, S. Mishra, S. Rastogi, V.
Zaca, H.N. Sabbah. Henry Ford Health System, Medicine, Detroit, United
States of America
Background: Neuregulin-1
(NRG-1) receptors ErbB2 and ErbB4 are localized in cardiomyocytes. Binding
of NRG-1 to its receptors activates Akt which, in turn, phosphorylates
endothelial nitric oxide synthase (eNOS) leading to increased nitric oxide
(NO) production and cardioprotection. In failed human hearts, expression
and phosphorylation (activation) of ErbB2 and ErbB4 receptors are
down-regulated. Disabling NRG-1 receptor signaling enhances apoptotic
susceptibility, promotes transition from compensatory hypertrophy to heart
failure (HF) and worsens the existing HF state. We previously showed that
chronic (3 months) therapy with electric Vagus nerve stimulation (VNS)
using the CardioFit System (BioControl Medical, Ltd.), improves LV
function in dogs with microembolization-induced HF. This study examined
the effects of long-term VNS therapy on mRNA expression of ErbB2 and ErbB4
and protein expression of phosphorylated ErbB2 (P-ErbB2), ErbB4 (P-ErbB4)
and Akt (P-Akt) in LV of dogs with chronic HF.
Methods: RNA was
extracted and homogenate prepared from LV tissue of 7 VNS-treated HF dogs,
6 untreated HF dogs (HF-Controls) and 6 normal (NL) dogs. mRNA expression
of ErbB2 and ErbB4 was measured using RT-PCR and protein expression of
P-ErbB2, P-ErbB4 and P-Akt was measured by Western blotting. Bands were
quantified in densitometric units (du).
Results: The data are
shown in the table. mRNA expression of ErbB2 and ErbB4 decreased in
HF-Controls compared to NL dogs as did P-ErbB2, P-ErbB4 and P-Akt. VNS
therapy normalized mRNA expression of ErbB2 and ErbB4 and protein
expression of P-ErbB2, P-ErbB4 and P-Akt.
| NL | HF-Controls | HF + VNS | |
|---|---|---|---|
| ErbB2 mRNA (du) | 1.50 ± 0.11 | 0.58 ± 0.06* | 1.38 ± 0.10† |
| ErbB4 mRNA (du) | 1.59 ± 0.08 | 0.43 ± 0.09 | 1.16 ± 0.11*† |
| P-ErbB2 (du) | 75 ± 1 | 60 ± 4* | 79 ± 6† |
| P-ErbB4 (du) | 60 ± 3 | 43 ± 2* | 64 ± 5† |
| P-Akt (du) | 51 ± 3 | 22 ± 2* | 49 ± 8† |
*=p<0.05 vs. NL; †=p<0.05 vs. HF-Controls
Conclusions: VNS therapy with CardioFit normalizes mRNA expression and restores NRG-1 receptors and Akt activity. Re-enabling of NRG-1 signaling pathway promotes cardioprotection and prevents worsening HF. These findings are consistent with the observed improvement of LV function in HF dogs chronically treated with VNS therapy.
Session Info: Poster session 4
Citation: Eur Heart J 2006, 27(Abstract Suppl), 476