Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice

Area of Science:

• Cardiovascular Physiology
• Neurogenetics
• Molecular Biology

Background:

• Brain-derived neurotrophic factor (BDNF) is crucial for neuronal and cardiovascular health.
• A common BDNF polymorphism (Val66Met) is linked to cardiometabolic disorders and cardiovascular disease.
• Previous studies indicated altered cardiac function in mice with the Val66Met polymorphism.

Purpose of the Study:

• To investigate the underlying mechanisms of cardiac dysfunction associated with the BDNF Val66Met polymorphism.
• To identify sex-based differences in cardiac physiology influenced by the BDNF Val66Met polymorphism.

Main Methods:

• Echocardiography was used to assess cardiac function in male and female mice with Val/Val, Val/Met, and Met/Met genotypes.
• Deep sequencing of RNA from whole hearts was performed to analyze gene expression profiles.
• Comparative analysis of cardiac parameters and transcriptomic data between sexes and genotypes.

Main Results:

• Female mice with the Val66Met polymorphism exhibited significant female-specific cardiac alterations, including increased chamber dimensions and stroke volume, with preserved ejection fraction.
• Both sexes showed reduced heart rates, more pronounced in females. SERCA2 (Atp2a2) expression was reduced, particularly in females.
• Female Met allele carriers displayed cardiac hypertrophy signatures (Tcap down-regulation, Nppb up-regulation), while males showed an inflammatory profile (IFN-γ-mediated Th1 response).

Conclusions:

• The BDNF Val66Met polymorphism induces sex-specific modifications in cardiac physiology.
• Females show altered cardiac structure and function, linked to specific cardiac gene expression changes.
• Males exhibit a distinct inflammatory response, highlighting the critical role of sex in BDNF's cardiovascular effects.