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Updated: Jun 25, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Leptin attenuates cardiac apoptosis after chronic ischaemic injury
Kenneth R McGaffin1, Baobo Zou, Charles F McTiernan
1Cardiovascular Institute, University of Pittsburgh Medical Center, 1750 Bioscience Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. mcgaffinkr@upmc.edu
Insights
Leptin signaling protects the heart from cell death after myocardial infarction (MI) by activating STAT-3 to increase anti-apoptotic genes and reduce caspase-3 activity. This highlights leptin
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Apoptosis Research
Background:
- Leptin signaling has been shown to reduce cardiac morbidity and mortality post-myocardial infarction (MI).
- The precise mechanisms by which leptin signaling confers cardioprotection remain under investigation.
- Understanding leptin's role in limiting cardiac apoptosis is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To test the hypothesis that leptin signaling limits cardiac apoptosis after MI.
- To investigate the role of signal transducer and activator of transcription (STAT)-3 in mediating leptin's anti-apoptotic effects.
- To examine the expression of key apoptosis-related genes, including B-cell lymphoma (bcl)-2 and survivin, and their regulation by leptin.
Main Methods:
- Comparison of cardiac apoptosis rates in wild-type and leptin-deficient (Ob/Ob) mice after MI.
- Assessment of inflammatory and apoptotic cell numbers via immunostaining.
- Quantification of cardiac bcl-2, survivin, and caspase-3 expression and activity.
- Inhibition of STAT-3 signaling using WP1066 in wild-type mice.
Main Results:
- Leptin-deficient mice exhibited increased cardiac apoptosis, particularly in infarcted regions, compared to wild-type mice.
- STAT-3 inhibition blunted anti-apoptotic gene expression (bcl-2, survivin) and increased caspase-3 activity in hearts.
- Leptin repletion in Ob/Ob mice significantly attenuated apoptosis post-MI, restoring levels to those seen in wild-type mice.
Conclusions:
- Intact leptin signaling post-MI is essential for limiting cardiac apoptosis.
- Leptin acts via STAT-3 to upregulate anti-apoptotic genes (bcl-2, survivin) and downregulate caspase-3 activity.
- These findings support a significant cardioprotective role for leptin in chronic ischemic injury.
Aims:
We have previously shown that activation of leptin signalling in the heart reduces cardiac morbidity and mortality after myocardial infarction (MI). In the present study, we tested the hypothesis that leptin signalling 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 And Results:
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 or sham operation. Inflammatory and apoptotic cell number was 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. In the absence of MI, both lean and obese leptin-deficient mice exhibited increased cardiac apoptosis compared with wild-type 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 wild-type 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 wild-type mice after MI.
Conclusion:
These results demonstrate that intact leptin signalling 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 ischaemic injury.
