Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

Abstract

Cardiac hypertrophy is an increase in the individual cellular volume of the heart and is an adaptive response to exogenous stresses. The increase in cellular volume is associated with reactivation of the fetal gene program, which is finely regulated by diverse cardiac transcription factors.1 Specifically, GATA4, GATA6, myocyte enhancer factor 2C, nuclear factor of activated T cells, NK2 homeobox 5, and serum response factor have been shown to be involved in the development of cardiac hypertrophy.1 GATA4 and GATA6 are heart-specific transcription factors that regulate pathological cardiac hypertrophy in association with atrial natriuretic factor (ANF) expression.2,3 Transgenic mice that overexpress GATA4 in the heart show cardiac hypertrophy, 4 and GATA4 activity is regulated by physical interaction with other transcription factors, such as serum response factor, NK2 homeobox 5, and myocyte enhancer factor 2.5-7 GATA6 also induces pathological cardiac hypertrophy, which was demonstrated by recent studies of cardiac-specific overexpression of GATA6 in mice. 3In addition to effects as transcription factors, some of these factors also act as nuclear receptors that provide signal-mediated responsiveness to endogenous or exogenous ligands. For example, peroxisome proliferator-activated receptor-α or steroid receptors respond to a ligand and then mediate diverse cellular events as well as metabolic regulation.8,9 Not surprisingly, these nuclear receptors also play important roles in various organs, and therapeutic applications of their modulators are growing. The nuclear receptors are classified depending on their structural similarities. Interestingly, 1 group of nuclear receptors is termed the orphan nuclear receptors. In contrast with the other nuclear receptors that have endogenous ligands

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart

“…Recently, roles for FXR in myocardial injury and SHP in cardiac hypertrophy have been identified. Hence, we examined whether deletion of Fxr or Shp alone led to the altered metabolic gene expression profile in DKO mice.…”

“…On the contrary, deletion of SHP causes hypertrophy and bradycardia, along with a few changes in the metabolic gene expression pattern compared to DKO mice (http://onlinelibrary.wiley.com/doi/10.1002/hep.28890/suppinfo). Our data validate the recently described role for SHP in regulating cardiac growth . It was shown that SHP is a novel antihypertrophic regulator that acts by interfering with GATA6 signaling in the heart .…”

“…Our data validate the recently described role for SHP in regulating cardiac growth . It was shown that SHP is a novel antihypertrophic regulator that acts by interfering with GATA6 signaling in the heart . Further studies in cardiomyocyte‐specific Fxr and Shp single and double knockouts would be necessary to fully delineate the role of the FXR–SHP axis in the heart.…”

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…Although these signaling cascades likely regulate GATA6 PTMs, as of yet, none have been specifically associated with cardiac adaptive stress response, although S290 phosphorylation by AKT2 and direct interaction with the HAT P300 have been reported in VSMCs . GATA6 interacting proteins in the adaptive stress response include small heterodimer partner (a GATA6 repressor), and interestingly, GATA4 (Table ) . Although the role of these heterotypic GATA interactions in cardiac hypertrophy have not been elucidated, GATA6 and 4 synergize to transactivate natriuretic factors genes whose upregulation is a hallmark of cardiac hypertrophy …”

“…78,79 GATA6 interacting proteins in the adaptive stress response include small heterodimer partner (a GATA6 repressor), and interestingly, GATA4 (Table 4). 44,77,80 Although the role of these heterotypic GATA interactions in cardiac hypertrophy have not been elucidated, GATA6 and 4 synergize to transactivate natriuretic factors genes whose upregulation is a hallmark of cardiac hypertrophy. 44,77 The findings regarding GATA6 and 4 in hypertrophy are especially notable because of their apparent overlap in function.…”