期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：1880-1885
DOI：10.1073/pnas.1417949112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceBDNF plays a key role in neuron development, survival, and function, with actions occurring through the stimulation of the tropomyosin-related kinase receptor B (TrkB) receptor. Whether BDNF/TrkB signaling has any physiologic role in governing myocardial function is unknown. Here we report that intact BDNF/TrkB signaling is required for the heart to fully contract and relax. These actions occur independently from and in addition to {beta}-adrenergic influence. BDNF-induced enhancement of myocardial performance occurs via direct modulation of Ca2+ cycling in a calmodulin-dependent protein kinase II-dependent manner. Thus, BDNF/TrkB signaling represents a previously unidentified way by which the peripheral nervous system controls cardiac muscle physiology. Our study suggests that loss or alterations in BDNF/TrkB stimulation may contribute to the pathogenesis of myocardial dysfunction in acute or chronic disease conditions. BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB-/-) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca2+ cycling, contractility, and relaxation via Ca2+/calmodulin-dependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with {beta}-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction.
