Abstract 15699: Metformin Mediated Restoration of Small Heterodimer Partner Negatively Regulates Cardiac Hypertrophy
Background: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor lacking DNA binding domain. SHP directly modulates the activities of other nuclear receptors and regulates a variety of cellular events such as cell differentiation, proliferation, and metabolism in various tissues. However, the role of SHP in heart has not yet been elucidated. Thus, in this study, we tried to investigate the functional roles of SHP in heart physiology and in the development of cardiac hypertrophy.
Methods and Results: We observed that SHP knock-out mice elicited cardiac hypertrophic features determined by heart weight to body weight or to tibia length ratios. Fetal genes, such as atrial natriuretic factor (ANF) or beta myosin heavy chain (βMHC) were significantly up-regulated in SHP knockout mice heart. In neonatal rat ventricular cardiomyocytes (NRVCs), phenylephrine (PE) reduced promoter activation of SHP and decreased protein level of SHP. Adenovirus-mediated over-expression of SHP (Adeno-SHP) significantly reduced hypertrophic responses induced by PE as assayed by [3H]-leucine incorporation, and cell size measurement in adult rat ventricular cardiomyocytes (ARVCs). Adeno-SHP significantly reduced hypertrophy-associated proteins. In contrast, knock-down of SHP by small hairpin RNA, decreased both Myh7 and Nppa promoter activities, whereas it up-regulated ANF or α-tubulin expressions. Metfomin (N,N-Dimethylimidodicarbonimidic diamide), an anti-diabetic agent, up-regulated SHP in dose-response fashion. PE-induced hypertrophy was significantly attenuated by metformin. However, metformin-mediated antihypertrophic action was not observed when the SHP was down-regulated by small interfering RNA against to SHP.
Conclusions: These results suggest that atypical orphan nuclear receptor SHP prevents cardiac hypertrophy and it mediates metformin-mediated antihypertrophic responses, implicating that theses signal cascades may serve as a novel therapeutic target of treatment of hypertrophic cardiomyopathy patients.
- © 2013 by American Heart Association, Inc.