Abstract 16549: Bdnf Protects the Heart Against Pressure Overload via Pgc-1a Mediated Signaling
Background: Current management of patients with heart failure (HF) largely focuses on limiting the adverse effects of sympathetic neurohormonal overdrive. However, the heart is also under the influence of neurotrophic factors. Brain-Derived Neurotrophic Factor (BDNF) is central to heart development: BDNF-/- mice display cardiac defects that are incompatible with post-natal life. Yet, whether BDNF signaling plays a major role in governing cardiac function in the adult life, particularly in response to stress, is still unclear.
Hypothesis: BDNF signaling contributes to maintain proper cardiac structure/function in pressure overloaded mice.
Results: BDNF expression is markedly down-regulated in hearts subjected to transverse aortic constriction (TAC). Forced BDNF over-expression by developing a cardiac-selective BDNF transgenic mice (BDNFtg) prevents from HF against pressure overload (fractional shortening (FS) = 49.9±2.25% in BDNFtg vs 28.3±7.3% in WT mice, n=5, p<0.05). Consistently, BDNF mimetic agonist LM22A4 also retards the HF progression in TAC mice with FS at 44±5 vs. 22±7% in vehicle group (n=8, P<0.05). In neurons, BDNF up-regulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) that rules energy metabolism and mitochondrial function, promoting dendritic spine formation. Oxidative stress is a major negative modulator of PGC-1a expression/activity. Exposing neonatal rat ventricular myocytes (NRVMs) to BDNF restored the downregulation of PGC-1a by hydrogen peroxide with a concomitant up-regulation of downstream genes involved both in mitochondrial biogenesis and oxidative stress, resulting in attenuated ROS production measured by EPR spectroscopy and increased mitochondrial biogenesis assessed by cytochrome C/beta-actin DNA ratio. These same genes were all up-regulated also in BDNFtg TAC mice, likely accounting for BDNF-induced protection.
Conclusion: Our data showed that BDNF confers protection against pressure overload via enhanced PGC-1a signaling that in turn prevents oxidative stress and improves mitochondrial biogenesis. Our studies suggest that BDNF/trkB is a new promising therapeutic avenue to prevent or retard heart failure.
- Heart failure
- Oxidative stress
- Mitochondrial energetics, heart failure, arrhythmias
- Cell signaling
- © 2013 by American Heart Association, Inc.