Abstract
Adult hearts respond to increased workload such as prolonged stress or injury, by undergoing hypertrophic growth. During this process, the early adaptive responses are important for maintaining cardiac output whereas at later stages, pathological responses such as cardiomyocyte apoptosis and fibrosis cause adverse remodelling, that can progress to heart failure. Yet the factors that control transition from adaptive responses to pathological remodelling in the heart are not well understood. Here we describe the POU4F2/Brn-3b transcription factor (TF) as a novel regulator of adaptive hypertrophic responses in adult hearts since Brn-3b mRNA and protein are increased in angiotensin-II (AngII) treated mouse hearts with concomitant hypertrophic changes [increased heart weight:body weight (HW:BW) ratio]. These effects occur specifically in cardiomyocytes because Brn-3b expression is increased in AngII-treated primary cultures of neonatal rat ventricular myocytes (NRVM) or foetal heart-derived H9c2 cells, which undergo characteristic sarcomeric re-organisation seen in hypertrophic myocytes and express hypertrophic markers, ANP/βMHC. The Brn-3b promoter is activated by known hypertrophic signalling pathways e.g. p42/p44 mitogen-activated protein kinase (MAPK/ERK1/2) or calcineurin (via NFAT). Brn-3b target genes, e.g. cyclin D1, GLUT4 and Bax, are increased at different stages following AngII treatment, supporting distinct roles in cardiac responses to stress. Furthermore, hearts from male Brn-3b KO mutant mice display contractile dysfunction at baseline but also attenuated hypertrophic responses to AngII treatment. Hearts from AngII-treated male Brn-3b KO mice develop further contractile dysfunction linked to extensive fibrosis/remodelling. Moreover, known Brn-3b target genes, e.g. GLUT4, are reduced in AngII-treated Brn-3b KO hearts, suggesting that Brn-3b and its target genes are important in driving adaptive hypertrophic responses in stressed heart.
Highlights
Differentiated cardiomyocytes in adult hearts respond to increased workload or chronic haemodynamic stress by undergoing hypertrophy
AngII stimulates Brn-3b expression in hypertrophic cardiomyocytes Since Brn-3b re-expression in injured adult hearts affects gene expression and cell fate[40], we tested if this transcription factor (TF) is increased in response to stimuli that induce hypertrophic responses in the heart
AngII-treated hearts expressed increased Brn-3b mRNA (Fig. 1b) whereas western blot analysis confirmed that similar increases in Brn-3b protein, correlated with induction of hypertrophic marker β-myosin heavy chain (β-MHC) (Fig. 1c)
Summary
Differentiated cardiomyocytes in adult hearts respond to increased workload or chronic haemodynamic stress by undergoing hypertrophy. Sustained pathological stresses, which can be induced by different stressors including neurohumoral activation (e.g. AngII), volume/pressure overload (e.g. hypertension and aortic stenosis), or acute cardiac injury (e.g. myocardial infarction), can drive irreversible, pathological changes such as cardiomyocyte apoptosis, interstitial fibrosis and adverse remodelling that precede progression to heart failure[4,5]. Changes in the hypertrophic heart arise due to alterations in gene expression following the activation of wellcharacterised signalling pathways[6,7,8,9,10,11]. The vasoactive peptide, AngII, acts as a Gα(q)-coupled receptor agonist to activate different kinase pathways e.g. mitogen-activated protein kinase/extracellular signalregulated kinase1/2 (MAPK/ERK); c-Jun N-terminal kinase or p38 MAPK12,13, which in turn, converge on key master regulators to control gene expression[6,7,8,9,10,11]. The calcium-dependent protein phosphatase, calcineurin A (CnA), activates the nuclear factor of activated
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