Mechanisms underlying leptininduced cardioprotection.
Doctoral thesis, UCL (University College London).
BACKGROUND: The tissue damage resulting from myocardial ischaemia/reperfusion (I/R) leads to a large proportion of the deaths in the developed world. Even if patients survive a myocardial infarction, I/R injury is associated with decreased cardiac function and a higher incidence of morbidity, and consequently, a reduced quality of life. Leptin is a cytokine produced by white adipose tissue that has been shown to activate the PI3K-Akt and p44/42 MAPK signalling cascades and protect the murine myocardium. The studies described in this thesis focused on the molecular mechanisms underlying leptin-induced cardioprotection with particular reference to cell signalling. METHODS & RESULTS: Using an isolated rat heart model of I/R injury, it was confirmed that leptin given at reperfusion protects the myocardium. This protection was abolished by the administration of specific blockers of the survival kinases PI3K, JAK and p44/42 MAPK. The time-points at which maximal phosphorylation of Akt, p44/42 MAPK and STAT3 occur in response to leptin given at reperfusion were identified. The key role played by the leptin receptor in leptin-induced cardioprotection was established by employing the Zucker obese rat (fa/fa), which has a mutation in the leptin receptor, and its Zucker lean (fa/+) counterpart that possesses a functional OB-R. It was found that the Zucker fatty rats were non-responsive to leptin-induced cardioprotection. Furthermore, it was shown that whilst leptin inhibited mitochondrial permeability transition pore (MPTP) opening in cardiomyocytes from Wistar and Zucker lean rats, MPTP opening in OB-R deficient Zucker fatty rats was unaffected. Finally, leptin was shown to protect against ischaemia-reperfusion injury in an in vivo rat model of I/R injury. CONCLUSION: The present study has yielded information concerning the mechanisms underlying the cardioprotective actions of leptin; including the importance of the OB-R. Extending the studies employing in vivo models of I/R injury will assist in establishing the potential of leptin as a therapeutic agent.
|Title:||Mechanisms underlying leptininduced cardioprotection|
|Open access status:||An open access version is available from UCL Discovery|
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