Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes.
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.


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.
Xu
Fang-Ping
FP
Department of Pharmacology, Guangzhou Medical College, Guangzhou, China 510182.
Chen
Min-Sheng
MS
Wang
Yan-Zhen
YZ
Yi
Quan
Q
Lin
Shu-Bing
SB
Chen
Alex F
AF
Luo
Jian-Dong
JD
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D000077868:Atrasentan; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology; D002374:Catalase / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020738:Leptin / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009765:Obesity / Q000150:complications; D018384:Oxidative Stress; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D020738:Leptin; D011759:Pyrrolidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009320:Atrial Natriuretic Factor; D002374:Catalase; D000077868:Atrasentan