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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 20, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm023
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Leptin Signaling Reduces the Severity of Cardiac Dysfunction and Remodeling after Chronic Ischemic Injury

Kenneth R. McGaffina,*, Cheuk-Kwan Sunb,1, Jennifer J. Ragera, Lia C. Romanob, Baobo Zoub, Michael A. Mathiera, Robert M. O'Dohertyc, Charles F. McTiernana and Christopher P. O'Donnellb

a Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
b Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
c Division of Endocrinology and Metabolism, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

* Corresponding author: Tel.: 412-647-2345. Fax: 412-383-8857. Email: mcgaffinkr{at}upmc.edu

Aim: Leptin is elevated under conditions of both obesity and heart failure (HF), and activation of leptin receptor (ObR) signaling is known to increase in vivo cardiac contractility and to have anti-hypertrophic effects on the left ventricle (LV). However, it is unknown whether ObR signaling is altered in cardiomyocytes after myocardial infarction (MI) leading to HF, or if a deficiency in ObR signaling leads to worse HF.

Methods: In separate experimental protocols, C57BL/6J and leptin-deficient (ob/ob) mice underwent open-chest surgery to induce permanent left coronary artery ligation (CAL) or had a sham operation. Subgroups of ob/ob mice examined were lean (food-restricted), obese (food ad libitum), and leptin repleted. Four weeks post-surgery, cardiac structure and function was examined by echocardiography, and the activation of cardiac leptin signaling was characterized through quantitative PCR, Western blotting, and DNA binding activities.

Results: CAL produced echocardiographic evidence of HF in C57BL/6J mice, elevated circulating leptin, increased cardiomyocyte leptin and ObR expression, and activated myocardial signal transducer and activator of transcription-3 (STAT3). In leptin-deficient ob/ob mice, whether lean or obese, CAL caused increased hypertrophy and dilation, decreased contractility of the LV, and worsened survival relative to wild-type or leptin-repleted mice after CAL. In ob/ob mice, activation of cardiac STAT3 signaling after CAL is enhanced in the presence of leptin and parallels the induction of the STAT3-responsive genes, tissue-inhibitor of metalloproteinase-1 and heat shock protein-70.

Conclusions: These data demonstrate that HF increases ObR signaling in cardiomyocytes and that activation of ObR signaling improves functional outcomes in chronic ischemic injury leading to HF.

KEYWORDS heart failure; signal transduction; ischemia; cytokines; gene expression

Time for primary review: 41 days

1 Present address: Department of Surgery, Chang Gung University, Kaohsiung Medical Center, 123 Ta-Pai Road, Niao-Sung Hsiang, Kaohsiung Hsien 83301, Taiwan.


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