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.
Published Version
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