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Published on: June 3, 2018
Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury
Kenneth R McGaffin1, Cheuk-Kwan Sun, Jennifer J Rager
1Cardiovascular Institute, University of Pittsburgh Medical Center, 1750 Bioscience Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. mcgaffinkr@upmc.edu
Insights
Leptin receptor signaling in heart cells improves outcomes after heart attack. Blocking this pathway worsens heart failure and survival in mice with myocardial infarction.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Leptin levels rise in obesity and heart failure (HF).
- Leptin receptor (ObR) signaling enhances cardiac contractility and has anti-hypertrophic effects.
- The role of ObR signaling in cardiomyocytes post-myocardial infarction (MI) is unclear.
Purpose of the Study:
- Investigate ObR signaling alterations in cardiomyocytes after MI.
- Determine if ObR deficiency exacerbates HF post-MI.
Main Methods:
- Induce MI via coronary artery ligation (CAL) or sham surgery in C57BL/6J and leptin-deficient (ob/ob) mice.
- Assess cardiac function and structure using echocardiography 4 weeks post-surgery.
- Characterize leptin signaling activation via qPCR, Western blotting, and DNA-binding assays.
Main Results:
- CAL induced HF in C57BL/6J mice, increasing cardiac leptin/ObR and activating STAT3 signaling.
- Leptin-deficient ob/ob mice exhibited worsened hypertrophy, dilation, LV contractility, and survival post-MI.
- Leptin presence enhanced cardiac STAT3 activation in ob/ob mice post-MI.
Conclusions:
- Heart failure increases ObR signaling in cardiomyocytes.
- Activating ObR signaling improves functional outcomes in chronic ischemic heart injury.
Aims:
Leptin is elevated under conditions of both obesity and heart failure (HF), and activation of leptin receptor (ObR) signalling 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 signalling is altered in cardiomyocytes after myocardial infarction (MI) leading to HF, or if a deficiency in ObR signalling leads to worse HF.
Methods And Results:
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 signalling was characterized through quantitative PCR, western blotting, and DNA-binding activities. 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 wildtype or leptin-repleted mice after CAL. In ob/ob mice, activation of cardiac STAT3 signalling 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.
Conclusion:
These data demonstrate that HF increases ObR signalling in cardiomyocytes and that activation of ObR signalling improves functional outcomes in chronic ischaemic injury leading to HF.
