Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering with GATA6 Signaling
Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated.
Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy.
Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and by direct physical interaction with Gata6 interfered with the binding of Gata6 to GATA binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an anti-diabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced anti-hypertrophic effect was attenuated either by SHP siRNA in cardiomyocytes or in SHP null mice.
Conclusions: These results establish SHP as a novel anti-hypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced anti-hypertrophic response.
- Received May 15, 2014.
- Revision received July 9, 2014.
- Accepted July 11, 2014.