Abstract
Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.
Highlights
Brain-derived neurotrophic factor (BDNF) is the most abundant member of the nerve growth factor (NGF) family and critical for neuronal growth and function
Few studies have examined the effects of the rs6265 BDNF polymorphism on the heart [36,37], but we previously found that cardiomyocytes isolated from transgenic Val66Met mice exhibit reduced contractility [38]
The results of the current study bring this into focus, as the rs6265 polymorphism leads to disparate expression profiles in male and female mice
Summary
Brain-derived neurotrophic factor (BDNF) is the most abundant member of the nerve growth factor (NGF) family and critical for neuronal growth and function. ProBDNF binds with low affinity to a common NGF receptor (p75NTR ) [8,9], which dimerizes with sortilin and generally leads to apoptosis [10], a process important for neuronal pruning, especially during development [7,11–13]. MBDNF binds its specific tyrosine kinase receptor (TrkB) with high affinity, which homodimerizes and is phosphorylated, leading to the induction of three canonical signaling pathways (PI3K/ERK/PLCy) with generally “positive” outcomes for neuronal and other cell types [14–16]. Isolated murine cardiomyocytes were recently shown to produce and respond to BDNF via a truncated TrkB isoform [19,20], which unlike the full-length isoform lacks the kinase domain and was originally thought to function only as a negative “sink” for mBDNF signaling [21,22]. Cardiomyocyte-specific deletion of the truncated isoform of TrkB impairs calcium signaling, cardiac contraction, and regulation of Ca(2+ )/calmodulin-dependent protein kinase II (CAMKII) activity [20]
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