SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart

A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a me...

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Bibliographic Details
Published in:PloS one 2012-12, Vol.7 (12), p.e53395-e53395
Main Authors: Reineke, Erin L, York, Brian, Stashi, Erin, Chen, Xian, Tsimelzon, Anna, Xu, Jianming, Newgard, Christopher B, Taffet, George E, Taegtmeyer, Heinrich, Entman, Mark L, O'Malley, Bert W
Format: Article
Language:English
Subjects:
Ablation
Animals
Aorta
Biology
Cardiology
Cellular biology
DNA binding proteins
DNA microarrays
Fatty acids
Fetuses
Gene expression
Genes
Genomes
Genomics
Heart
Heart diseases
Heart failure
Heart Ventricles - metabolism
Heart Ventricles - physiopathology
Hypertrophy
Hypertrophy, Left Ventricular - genetics
Hypertrophy, Left Ventricular - metabolism
Hypertrophy, Left Ventricular - physiopathology
Insulin resistance
Medicine
Metabolism
Mice
Mice, Knockout
Myocardium - metabolism
Myocytes, Cardiac - metabolism
Nuclear Receptor Coactivator 2 - genetics
Nuclear Receptor Coactivator 2 - metabolism
Proteins
Rodents
Signaling
Stress response
Stresses
Transcription (Genetics)
Transcription factors
Ventricle
Ventricular Dysfunction, Left - genetics
Ventricular Dysfunction, Left - metabolism
Ventricular Dysfunction, Left - physiopathology
Ventricular Remodeling - genetics
Wall thickness
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Summary:A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a mechanistic role in the stress response and that SRC-2 activity is an important regulator of the adult heart gene expression profile. Genome-wide microarray analysis, confirmed with targeted gene expression analyses revealed that genetic ablation of SRC-2 activates the "fetal gene program" in adult mice as manifested by shifts in expression of a) metabolic and b) sarcomeric genes, as well as associated modulating transcription factors. While these gene expression changes were not accompanied by changes in left ventricular weight or cardiac function, imposition of transverse aortic constriction (TAC) predisposed SRC-2 knockout (KO) mice to stress-induced cardiac dysfunction. In addition, SRC-2 KO mice lacked the normal ventricular hypertrophic response as indicated through heart weight, left ventricular wall thickness, and blunted molecular signaling known to activate hypertrophy. Our results indicate that SRC-2 is involved in maintenance of the steady-state adult heart transcriptional profile, with its ablation inducing transcriptional changes that mimic a stressed heart. These results further suggest that SRC-2 deletion interferes with the timing and integration needed to respond efficiently to stress through disruption of metabolic and sarcomeric gene expression and hypertrophic signaling, the three key stress responsive pathways.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0053395