Abstract P226: Small Heterodimer Partner Negatively Regulates Cardiac Hypertrophy Through Upregulation of GATA6
Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that regulates a variety of cellular events such as cell proliferation, differentiation and metabolism in liver and bone. However, the role of SHP in heart has not yet been elucidated. In this study, we investigated the functional roles of SHP in cardiac hypertrophy. In rat neonatal cardiomyocytes model, phenylephrine (PE) down-regulated expression of SHP. Transient transfection of SHP decreased the promoter activity of Nppa (natriuretic polypeptide precursor type A). Adenovirus-mediated overexpression of SHP (Ad-SHP) blocked gene expressions of GATA4, GATA6, and serum response factor (SRF). The increase in [3H]-leucine incorporation induced by PE or fetal bovine serum (FBS) was dramatically reduced by Ad-SHP. Likewise, increases in cell size with those hypertrophic stresses were significantly attenuated by Ad-SHP. The expressions of atrial natriuretic factor (ANF), β-myosin heavy chain (βMHC), and skeletal α-actin were significantly higher in hearts of SHP null mice. SHP physically interacted with GATA6 in mammalian cells. SHP significantly decreased the activation of -3003 Nppa promoter induced by GATA6. The action of SHP on Nppa promoter activity was partially recovered by GATA6. Taken together, these results suggest that SHP works as a novel anti-hypertrophic regulator by repressing GATA6.
- © 2011 by American Heart Association, Inc.