Leptin Regulates Cardiomyocyte Contractile Function Through Endothelin-1 Receptor–NADPH Oxidase Pathway

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2006-02, Vol.47 (2), p.222-229
• Main Authors: Dong, Feng, Zhang, Xiaochun, Ren, Jun
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Calcium - metabolism; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cyclic N-Oxides - pharmacology; Endothelin A Receptor Antagonists; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Heart; Heart Ventricles; Intracellular Membranes - metabolism; Leptin - pharmacology; Leptin - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocytes, Cardiac - physiology; NADPH Oxidases - metabolism; Oligopeptides - pharmacology; Peptides, Cyclic - pharmacology; Piperidines - pharmacology; Receptor, Endothelin A - metabolism; Receptors, Leptin; Spin Labels; Superoxides - metabolism; Vertebrates: cardiovascular system
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000198555.51645.f1

Leptin, the obese gene product, plays an important role in the regulation of cardiac function. However, the mechanism behind leptin-induced cardiomyocyte contractile response is poorly understood. This study was designed to examine whether endothelin-1 receptor and NADPH oxidase play any role in leptin-induced cardiac contractile response. Isolated murine cardiomyocytes were exposed to leptin (5, 50, and 100 nmol/L) for 60 minutes in the absence or presence of the ETA receptor antagonist BQ123 (1 μmol/L), the ETB receptor antagonist BQ788 (1 μmol/L), or the NADPH oxidase inhibitor apocynin (100 μmol/L) before mechanical function was studied. Superoxide levels were measured by dihydroethidium fluorescent dye and the superoxide dismutase–inhibitable reduction of cytochrome c. NADPH oxidase subunit expression (p22, p47, p67, and gp91) was evaluated with Western blot. Leptin depressed peak shortening and maximal velocity of shortening/relengthening (±dL/dt), prolonged the duration of relengthening (TR90) without affecting the time-to-peak cell shortening. Consistent with the mechanical characteristics, myocytes treated with leptin displayed a reduced electrically stimulated rise in intracellular Ca (change in fura-2 fluorescence intensity) associated with a prolonged intracellular Ca decay rate. All of the abnormalities were significantly attenuated by apocynin, BQ123, or BQ788. Intracellular superoxide generation was enhanced after leptin treatment, which was partially blocked by apocynin, BQ123, or BQ788. Leptin had no effect on p22 and gp91 but upregulated protein expression of p67 and p47, both of which were inhibited by apocynin, BQ123, or BQ788. These results suggest that leptin suppresses cardiac contractile function in ventricular myocytes through the endothelin-1 receptor and NADPH oxidase-mediated pathway.