Abstract 340: Myocyte-borne Bdnf is Essential to Limit Post-ischemic Cardiac Injury and Dysfunction

Abstract

Brain-derived neurotrophic factor (BDNF)/ tyrosine receptor kinase B (TrkB) signaling is essential for normal cardiac contraction/relaxation. Alterations in this pathway, i.e., defective neuronal BDNF, account for post-ischemic cardiac injury. Less clear, however, is whether myocyte-borne BDNF has a role in this setting. We generated myocyte-selective BDNF knock-out (myoBDNF -/- ) mice, using Myh6-Cre mice crossed with BDNF floxed mice, confirming bdnf deletion via RT-PCR in isolated myocytes. Hearts from 12-wk old myoBDNF -/- mice and WT littermates underwent global ischemia (30 min) and reperfusion (2 h). At this age, the two strains had similar left ventricular (LV) sizes and fractional shortening [63±1.1 (WT) vs. 60±1.2% (myoBDNF -/- )]. At reperfusion, myoBDNF -/- hearts displayed larger infarct size compared to WT (38±3 vs. 14±2%, n=9, p<.0001) and worsened LV functional recovery ( Fig. 1 ). For example, the rate-pressure product recuperated only by 14±1.5 in myoBDNF -/- mice vs. 36±3% in WT (p<.0001). The two groups had similar heart rates at 2 h reperfusion, however myoBDNF -/- mice markedly lost their contractility [dP/dt max = 436±58 vs. 1407±142 mmHg/sec (WT), p< .0001], likely due to the exacerbated myocyte loss. Accordingly, post-ischemic troponin I release was significantly higher in myoBDNF -/- than in WT mice (0.9±0.04 vs. 1.3±0.04 ng/ml, p<.0002). Thus, deleting bdnf in myocytes severely limits recovery after ischemia, directly linking myocyte-borne BDNF to the heart response to injury. Therefore, preserving or enhancing autologous myocyte BDNF generation offers new avenues to counter cardiac ischemic injury and subsequent heart failure progression.