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(Circulation. 2004;110:1269-1275.)
© 2004 American Heart Association, Inc.

Original Articles

Leptin Induces Hypertrophy via Endothelin-1–Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes

Fang-Ping Xu, MD^*; Min-Sheng Chen, MD^*; Yan-Zhen Wang, MD; Quan Yi, MD; Shu-Bing Lin, MD; Alex F. Chen, MD, PhD; Jian-Dong Luo, MD, PhD

From the Departments of Pharmacology (F.-P.X., Q.Y., S.-B.L., J.-D.L.) and Internal Medicine (M.-S.C.), Guangzhou Medical College, Guangzhou, China; the Department of Research Laboratory of Pathophysiology, PLA General Hospital, Beijing (Y.-Z.W.), China; and Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, East Lansing, Mich (A.F.C., J.-D.L.). Dr Xu is now at the Department of Pathology, Preclinical Medicine School, Sun Yat-sen University, Guangzhou 510080, China.

Correspondence to Jian-Dong Luo, MD, PhD, Department of Pharmacology, Guangzhou Medical College, Guangzhou, China 510182. E-mail jiandongluo{at}hotmail.com

Received September 29, 2003; de novo received February 15, 2004; revision received April 29, 2004; accepted May 3, 2004.

Background— Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood.

Methods and Results— This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentration-dependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET_A receptor antagonist, ABT-627, and catalase, a hydrogen peroxide–decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment.

Conclusions— These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1–ET_A–ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET_A receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

Key Words: hypertrophy • endothelin • leptin • stress

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