POU4F2/Brn-3b transcription factor in cardiac hypertrophy

Pathological hypertrophy e.g. following myocardial infarction (MI), in response to persistent hypertension or in ischemic /non-ischemic cardiomyopathies contributes to cardiac dysfunction, arrhythmia and heart failure, but mechanisms underlying these maladaptive changes are not fully understood. However, specific molecular signatures such as re-expression of foetal gene expression pattern, correlates with hypertrophy. Our preliminary data show that transcription factor (TF), POU4F2/Brn-3b, which is expressed in developing hearts, may be involved in cardiac hypertrophy. Brn-3b transactivate multiple target genes, including cell cycle regulators, cyclinD1/CDK4, which are important for cardiac hypertrophy. The Brn-3b promoter is stimulated by the ERK/p42/p44-MAPK pathway, which is a key regulator of cardiac hypertrophy and bioinformatics analysis identified binding sites for cardiac TFs including GATA and NFAT (for calcineurin-mediated cardiac hypertrophy), suggesting Brn-3b as a putative downstream effector of these pathways. Preliminary in-vitro studies show that treatment of primary cardiomyocytes or H9c2 cells with hypertrophic stimulus angiotensin II increases Brn-3b expression. In-vivo studies using mouse models show that Brn-3b is upregulated in a compensatory manner in hearts lacking the related Brn-3a TF, which results in hyperplastic valves and ventricular septum, (possibly associated with increased proliferation), whereas, initial studies show that hearts from Brn-3b KO mutants have thinner ventricular wall at baseline and attenuated hypertrophic response to angiotensin II compared to control (WT) hearts. Bioinformatics analysis of microarray data also show increased Brn-3b in myocytes from patients with non-ischaemic hypertrophic cardiomyopathy, thus supporting possible roles for this TF in developmental and adaptive hypertrophy