Brain-derived Neurotrophic Factor Protects Against Cardiac Dysfunction after Myocardial Infarction via a Central Nervous System-mediated Pathway

The central nervous system is thought to affect cardiovascular regulation in response to various stimuli from peripheral tissues. However, the understanding of its molecular mechanisms is still limited. Here we demonstrate a novel CNS-mediated mechanism by which brain-derived neurotrophic factor (Bdnf) protects against cardiac remodeling after myocardial infarction (MI). We generated conditional Bdnf knockout (CKO) mice, in which expression of Bdnf was systemically reduced, by using the inducible Cre-loxP system. Then MI was induced surgically in these mice. Two weeks later, systolic function was significantly impaired and cardiac size was markedly increased in CKO mice compared with controls. Cardiomyocyte death was increased in these mice, along with decreased expression of survival molecules. Deletion of the Bdnf receptor TrkB in the heart also exacerbated cardiac dysfunction after MI. The plasma levels of Bdnf were markedly increased after MI and this increase was associated with up-regulation of Bdnf in the brain, but not in the heart. Ablation of afferent nerves from the heart or genetic disruption of neuronal Bdnf inhibited the increase of plasma Bdnf after MI and exacerbated cardiac dysfunction, suggesting that Bdnf expression is up-regulated by neural signals from the heart after MI and that this up-regulation protects the myocardium against ischemic injury. These findings also suggest that activation of neuronal Bdnf may have therapeutic significance for cardiac disease.