International Journal of Molecular Sciences | |
Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice | |
Eric C. Rouchka1  Julia L. Chariker1  Lauren E. Gansereit2  Gabrielle Kitchen2  Cristi L. Galindo2  Aaron Heck2  Imamulhaq Brula2  Marcus Negron2  Jeffrey Kristensen2  Van Thuan Nguyen2  Simran Banga2  Lin Zhong3  Frank J. Raucci3  Cassandra P. Awgulewitsch4  | |
[1] Computer Engineering and Computer Science, Kentucky Biomedical Research Infrastructure Network, University of Louisville, Louisville, KY 40202, USA;Department of Biology, Western Kentucky University, Bowling Green, KY 42101, USA;Department of Pediatrics, Division of Pediatric Cardiology, Children’s Hospital of Richmond, Virginia Commonwealth University, Richmond, VA 23219, USA;Vanderbilt University Medical Center, Division of Cardiovascular Medicine, Nashville, TN 37232, USA; | |
关键词: brain-derived neurotrophic growth factor; dilated cardiomyopathy; rs6265 polymorphism; Duchenne muscular dystrophy; Val66Met; | |
DOI : 10.3390/ijms22137002 | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown