Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp071
Leptin attenuates cardiac apoptosis after chronic ischemic injury
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
* Corresponding author: 1750 Bioscience Tower, 200 Lothrop Street, Pittsburgh, PA, 15213, USA. Tel.: 412-647-2345. Fax: 412-383-8857. Email: mcgaffinkr{at}upmc.edu
Aims: We have previously shown that activation of leptin signaling in the heart reduces cardiac morbidity and mortality after myocardial infarction (MI). In the present study, we tested the hypothesis that leptin signaling limits cardiac apoptosis after MI through activation of signal transducer and activator of transcription (STAT)-3 responsive anti-apoptotic genes, including B-cell lymphoma (bcl)-2 and survivin, that serve to downregulate the activity of caspase-3.
Methods: Hearts from C57BL/6J and three groups of leptin-deficient Ob/Ob mice (food-restricted, ad libitum, and leptin-repleted) were examined 4 weeks after permanent left coronary artery ligation (CAL) or sham operation. Inflammatory and apoptotic cell number were determined in cardiac sections by immunostaining. Expression of cardiac bcl-2, survivin, and pro and active caspase-3 was determined and correlated with in vitro caspase-3 activity.
Results: In the absence of MI, both lean and obese leptin-deficient mice exhibited increased cardiac apoptosis compared to wildtype mice. After MI, the highest rates of apoptosis were seen in the infarcted tissue of lean and obese Ob/Ob mice. Further, leptin-deficient hearts, as well as hearts from wildtype mice treated with the STAT-3 inhibitor WP1066, exhibited blunted anti-apoptotic bcl-2 and survivin gene expression, and increased caspase-3 protein expression and activity. The increased caspase-3 activity and apoptosis in hearts of leptin-deficient mice after MI was significantly attenuated in Ob/Ob mice replete with leptin, reducing apoptosis to levels comparable to that observed in wildtype mice after MI.
Conclusions: These results demonstrate that intact leptin signaling post-MI acts through STAT-3 to increase anti-apoptotic bcl-2 and survivin gene expression and reduces caspase-3 activity, consistent with a cardioprotective role of leptin in the setting of chronic ischemic injury.
KEYWORDS Apoptosis; leptin; survivin; bcl-2; heart failure
Time for primary review: 30 Days