Rationale A key feature of cardiovascular disease is cardiac hypertrophy, whereby terminally differentiated cardiomyocytes enlarge in response to stress. Hypertrophy can be beneficial to cardiac function (e.g., exercise or pregnancy); however pathological hypertrophy (e.g. chronic hypertension) is detrimental and leads to heart failure. The fate of cardiomyocytes during hypertrophy are dependent gene expression changes. Hence, cardiac transcription factors that control such changes by regulating target genes will be important for facilitating hypertrophy. The transcription factor POU4F2/Brn3b is highly expressed in the foetal heart and reduced in adult cardiomyocytes but is re-expressed in response to injury. Its interaction with other proteins such as the oestrogen receptor differentially regulate transcriptional activity; suggesting a difference in adaptation to physiological and pathological stress in male and female mice.
Methods and results Male and female Brn3b-KO mutant mice and wild type controls were used to assess the role of this TF in physiological (exercise on running wheels) and pathological stress (Angiotensin II infusion). Changes in cardiac function (cardiac output, etc.) were analysed using echocardiography/ultrasound, histological changes were assessed (e.g. Masson’s Trichrome) and genetic changes (e.g. qPCR, Western blot) were measured at baseline and 4 weeks post treatment. Following pathological and physiological stress, cardiac function and contractility were reduced in male Brn3b-KO mice compared to baseline measurements. Exercise performance in Brn3b KO male mice was also reduced compared to WT mice. In contrast, cardiac function and contractility were not compromised in Brn3b KO female mice following physiological and pathological stress compared to baseline measurements. In addition, exercise performance in Brn3b KO female mice was better when compared to WT mice.
Conclusion Brn3b may be important for the adaptive hypertrophic response in male mice, but not necessary for female mice, suggesting complex roles for Brn3b in the stressed heart.
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