Abstract
We have previously demonstrated the potential role of steroid receptor coactivator-2 (SRC-2) as a co-regulator in the transcription of critical molecules modulating cardiac function and metabolism in normal and stressed hearts. The present study seeks to extend the previous information by demonstrating SRC-2 fulfills this role by serving as a critical coactivator for the transcription and activity of critical transcription factors known to control cardiac growth and metabolism as well as in their downstream signaling. This knowledge broadens our understanding of the mechanism by which SRC-2 acts in normal and stressed hearts and allows further investigation of the transcriptional modifications mediating different types and degrees of cardiac stress. Moreover, the genetic manipulation of SRC-2 in this study is specific for the heart and thereby eliminating potential indirect effects of SRC-2 deletion in other organs. We have shown that SRC-2 is critical to transcriptional control modulated by MEF2, GATA-4, and Tbx5, thereby enhancing gene expression associated with cardiac growth. Additionally, we describe SRC-2 as a novel regulator of PPARα expression, thus controlling critical steps in metabolic gene expression. We conclude that through regulation of cardiac transcription factor expression and activity, SRC-2 is a critical transcriptional regulator of genes important for cardiac growth, structure, and metabolism, three of the main pathways altered during the cardiac stress response.
Highlights
An efficient cardiac stress response requires a series of coordinated molecular changes
We have shown that Steroid receptor coactivator-2 (SRC-2) is critical to transcriptional control modulated by myocyte enhancer factor 2 (MEF2), GATA-4, and Tbx5, thereby enhancing gene expression associated with cardiac growth
We identified a novel mechanism by which SRC-2 acts as a major regulator of the cardiac transcription program through control of widespread cardiac transcription factor expression, as well as through coactivation of key cardiac transcription factors MEF2, GATA-4, and Tbx5
Summary
An efficient cardiac stress response requires a series of coordinated molecular changes. Transcriptional cross-talk occurs between MEF2, GATA-4, and other cardiac transcription factors, including NK2 homeobox 5 (Nkx2.5), serum response factor (SRF), and Tbx5 This coordinated control shows extensive target gene overlap among the factors, as well as control of several targets of similar signaling pathways [2,3,4,5,6,7]. The onset of cardiac stress via transverse aortic constriction results in decreased function in hearts lacking SRC-2, and a normal hypertrophic response does not occur [17] These data suggest an important role for SRC-2 in regulating cardiac gene expression, but fail to delineate genes directly controlled by SRC-2 from compensatory changes due to stress or what factor(s) SRC-2 works with on those genes because it cannot directly bind DNA. It serves as a coordinator of transcription during the cardiac stress response
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