Key result
TrkB agonists and β3AR stimulation reduce infarct size and improve post-MI LV dysfunction by replenishing BDNF.
Why the study?
It was unclear if β-adrenergic receptor stimulation enhances cardiac BDNF expression post-ischemia, and whether TrkB agonists counter chronic postischemic LV decompensation.
TrkB agonists and β3AR stimulation (or β1-blockade via β3AR upregulation) can improve chronic postischemic left ventricular dysfunction by replenishing myocardial BDNF.
Hypothesis-generating for BDNF modulation in postischemic HF; leaves open translation to human therapy.
BACKGROUND: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the β-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. METHODS: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, β3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). RESULTS: In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the β3AR-agonist, BRL-37344, increased myocyte BDNF content, while β3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the β1AR blocker, metoprolol, via upregulated β3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. CONCLUSIONS: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac β3AR stimulation, or β-blockers (via upregulated β3AR), is another BDNF-based means to fend off chronic postischemic heart failure.
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Cannavò et al. (2023) studied Chronic postischemic heart failure. TrkB agonists (LM22A-4) and β3AR agonists (BRL-37344) vs. Vehicle or sham operation was evaluated on Infarct size and left ventricular function. TrkB agonists and β3AR stimulation mitigated infarct size and improved chronic post-ischemic left ventricular dysfunction by replenishing myocardial brain-derived neurotrophic factor (BDNF).
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