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

Abstract

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 concentrationdependent 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.

Role of resistin in cardiac contractility and hypertrophy

“…However, recent studies have determined that adipose tissue synthesizes and secretes a number of bioactive molecules that have the ability not only to contribute to the pathogenesis of insulin resistance but also to modulate cardiac remodeling. In addition to resistin, as shown in the present study, leptin has also been reported to promote cardiac hypertrophy [43], [44] through a mechanism involving MAPKs, similar to resistin. In contrast, adiponectin was shown to inhibit cardiac hypertrophy possibly through the activation of AMPK (AMP-activated protein kinase) signaling [45].…”

Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity

“…We (7) have previously demonstrated that leptin deficiency contributes to LVH in vivo in intact ob͞ob mice with established LVH. On the other hand, in normal neonatal myocytes, exposure to leptin in vitro stimulates growth or hypertrophy (21,22). However, these findings are not incompatible with each other, as the observed dichotomy could easily arise because of differences in milieu.…”

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

“…Cardiovascular regulation of the obese gene product leptin has attracted much attention because its deficiency or resistance leads to obesity and cardiovascular problems [3][4][5][6]. Leptin receptors exist in cardiomyocytes and are coupled to the signalling pathways regulating myocardial contractility [6,7] and cellular growth [5,8]. Mice lacking leptin (Lep/ Lep, formerly known as ob/ob) or its receptor (Lepr/Lepr, formerly known as db/db) develop cardiac hypertrophy and contractile dysfunction, consolidating a role for leptin in the maintenance of cardiac architecture and function [5,9,10].…”