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Publication
Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met
Mice.
Authors Negron M, Kristensen J, Nguyen VT, Gansereit LE, Raucci FJ, Chariker JL, Heck A,
Brula I, Kitchen G, Awgulewitsch CP, Zhong L, Rouchka EC, Banga S, Galindo CL
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal International journal of molecular sciences
Year 2021
Date Published 6/1/2021
Volume : Pages 22 : Not Specified
PubMed Reference 34210092
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-? (IFN-?)-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.




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