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(Hypertension. 2006;47:222.)
© 2006 American Heart Association, Inc.

Original Articles

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

From the Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyo.

Correspondence to Professor Jun Ren, Center for Cardiovascular Research and Alternative Medicine and Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071. E-mail jren{at}uwyo.edu

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 ET_A receptor antagonist BQ123 (1 µmol/L), the ET_B 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^phox, p47^phox, p67^phox, and gp91^phox) 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 Ca²⁺ (change in fura-2 fluorescence intensity) associated with a prolonged intracellular Ca²⁺ 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^phox and gp91^phox but upregulated protein expression of p67^phox and p47^phox, 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.

Key Words: endothelin • cardiac function • obesity • oxidative stress

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