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1 Division of Translational Research, Kyoto Medical Center, Kyoto, Kyoto, Japan
2 Department of Cardiovascular Medicine, Kyoto University, Kyoto, Kyoto, Japan
3 Division of Translational Research, Kyoto Medical Center, Kyoto, Kyoto, Japan; Kyoto, Japan
4 Division of Translational Research, Kyoto Medical Center, Kyoto, Kyoto, Japan; Kyoto, Kyoto, Japan
* To whom correspondence should be addressed. E-mail: kohono{at}kuhp.kyoto-u.ac.jp.
One of the major manifestations of obesity is an increased production of the adipocyte-derived 16-kDa peptide leptin, which acts mainly on hypothalamic leptin receptors. Leptin receptors are widely distributed in various tissues, including the heart. While increased plasma leptin levels have been reported in patients with congestive heart failure, systemic alterations induced by obesity can affect cardiac hypertrophy and the direct effects of leptin on cardiac structure and function still remain to be determined. We first exposed primary cardiac myocytes from neonatal rats to leptin for 48 hours. This resulted in a significant increase in myocyte long-axis length (p<0.05 at 50ng/mL), but not in the short-axis width. Leptin induced the rapid phosphorylation of STAT3 and its DNA binding in cardiac myocytes. Administration of a JAK2 inhibitor, AG490, completely inhibited all of these effects by leptin. Furthermore, we examined the effect of continuous infusion of leptin for four weeks following myocardial infarction (MI) in mice. Echocardiography demonstrated that left ventricular fractional shortening in the leptin-infused group (28.4±2.8%) was significantly higher than that in the PBS-infused group (18.4±2.2%) following MI. Interestingly, LV diastolic dimension in the leptin-infused group (4.56±0.12 mm) was also higher than that in the PBS-infused group (4.13±0.09 mm). These results demonstrate that leptin induces the elongation of cardiac myocytes via a JAK/STAT pathway and chronic leptin infusion causes eccentric dilatation with augmented systolic function after myocardial infarction.
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