Yoon Seok Nam¹, Yoojung Kim¹, Hosouk Joung¹, Duk-Hwa Kwon¹, Nakwon Choe¹, Hyun-Ki Min¹, Yongsook Kim², Hyung Seok Kim³, Don-Kyu Kim⁴, Young Kuk Cho⁵, Yong Hoon Kim⁶, Kwang-Il Nam⁷, Hyoung Chul Choi⁸, Dong Ho Park⁹, Kyoungho Suk¹⁰, In-Kyu Lee¹¹, Youngkeun Ahn², Chul-Ho Lee⁶, Hueng-Sik Choi⁴, Gwang Hyeon Eom¹ and Hyun Kook^1*

¹Medical Research Center for Gene Regulation, Chonnam National University Medical School
²Cardiology, Chonnam National University Hospital
³Forensic Medicine, Chonnam National University Medical School
⁴National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, Chonnam National University
⁵Pediatrics, Chonnam National University Hospital
⁶Korea Research Institute of Bioscience and Biotechnology
⁷Anatomy, Chonnam National University Medical School
⁸Pharmacology, Yeungnam University
⁹Ophthalmology, Kyungpook National University School of Medicine
¹⁰Pharmacology, Kyungpook National University School of Medicine
¹¹Internal Medicine, Kyungpook National University School of Medicine

Author Contributions: H.K. and G.H.E. are co-corresponding authors.

Abstract
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.

Key Words : small heterodimer partner, orphan nuclear receptor, metformin, GATA6, cardiac hypertrophy, hypertrophy