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1 Division of Cardiology
2 Division of Pulmonary Medicine, Department of Medicine
3 Department of Anaesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
4 Department of Anaesthesiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Impaired leptin signalling in obesity is increasingly implicated in cardiovascular pathophysiology. To explore mechanisms for leptin activity in the heart, we hypothesized that physiological leptin signalling participates in maintaining cardiac ß-adrenergic regulation of excitation–contraction coupling. We studied 10-week-old (before development of cardiac hypertrophy) leptin-deficient (ob/ob, n = 12) and C57Bl/6 (wild-type (WT), n = 15) mice at baseline and after recombinant leptin infusion (0.3 mg kg–1 day–1 for 28 days, n = 6 in each group). Ob/ob-isolated myocytes had attenuated sarcomere shortening and calcium transients ([Ca2+]i) versus WT (P < 0.01 for both) following stimulation of the ß-receptor (with isoproterenol (isoprenaline)) or at the post-receptor level (with forskolin and dibutryl-cAMP). In addition, sarcoplasmic reticulum (SR) Ca2+ stores were depressed. Leptin replenishment in ob/ob mice restored each of these abnormalities towards normal without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture. Immunoblots revealed alterations of several proteins involved in excitation–contraction coupling in the ob/ob mice, including decreased abundance of Gs
-52 kDa, as well as alterations in the expression of Ca2+ cycling proteins (increased SR Ca2+-ATPase, and depressed phosphorylated phospholamban). In addition, protein kinase A (PKA) activity in ob/ob mice was depressed at baseline and correctable towards the activity found in WT with leptin repletion, a finding that could account for impaired ß-adrenergic responsiveness. Taken together, these data reveal a novel link between the leptin signalling pathway and normal cardiac function and suggest a mechanism by which leptin deficiency or resistance may lead to cardiac depression.
(Received 16 February 2005;
accepted after revision 7 March 2005;
first published online 10 March 2005)
Corresponding author J. M. Hare: The Johns Hopkins Medical Institutions, Cardiology Division, 720 Rutland Avenue, Ross 1059, Baltimore, MD 21205, USA. Email: jhare{at}mail.jhmi.edu
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