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β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.
Alessandro Cannavo1,2, Seungho Jun1,3, Giuseppe Rengo1,4
1Department of Translational Medical Science (A.C., G.R., F.M., D.L., A.E., N. Ferrara), University of Naples Federico II, Italy.
Circulation Research
|March 8, 2023
Summary
Loss of brain-derived neurotrophic factor (BDNF) signaling contributes to heart disorders. TrkB agonists and beta-adrenergic receptor stimulation can restore BDNF levels, improving cardiac function after myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Neurobiology
- Molecular Medicine
Background:
- Brain-derived neurotrophic factor (BDNF)/TrkB signaling is crucial for neuronal and cardiac health.
- Dysfunctional BDNF/TrkB signaling contributes to heart disorders, particularly after myocardial ischemia.
- The role of BDNF in the postischemic heart and the therapeutic potential of TrkB agonists remain incompletely understood.
Purpose of the Study:
- To investigate the role of BDNF in the postischemic myocardium.
- To determine if TrkB agonists can counteract chronic left ventricle (LV) decompensation following myocardial infarction.
- To explore the interplay between beta-adrenergic receptor stimulation and BDNF production in the heart.
Main Methods:
- In vitro studies using cardiomyocytes, neuronal cells, and endothelial cells.
- In vivo assessment of myocardial ischemia (MI) in wild type and genetically modified mice (β3AR knockout, myocyte-selective BDNF knockout).
- Evaluation of isolated hearts subjected to global ischemia-reperfusion (I/R) injury.
Main Results:
- Myocardial BDNF levels decreased significantly at 4 weeks post-MI, coinciding with LV dysfunction.
- The TrkB agonist LM22A-4 improved cardiac function, reduced infarct size, and promoted neovascularization.
- Beta-3 adrenergic receptor (β3AR) stimulation increased myocyte BDNF content, offering protection against I/R injury.
- Beta-1 adrenergic receptor (β1AR) blockers, like metoprolol, improved chronic post-MI LV dysfunction by upregulating β3ARs and increasing myocardial BDNF.
Conclusions:
- Loss of BDNF signaling contributes to chronic heart failure after ischemia.
- TrkB agonists represent a potential therapeutic strategy to improve ischemic LV dysfunction by restoring myocardial BDNF.
- Targeting cardiac β3ARs, either directly or indirectly via β-blockers, offers a novel BDNF-dependent approach to combat chronic postischemic heart failure.
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