Anastasios, C.; (2007) Effects of the urocortin family of peptides on cardiac neonatal myocytes, antiapoptotic and hypertrophic effects. Doctoral thesis , University of London.

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Abstract

Urocortin 1 (UCN) and its homologues Urocortin 2 (UCN2/SRP) and urocortin 3 (UCN3/SCP) belong to the corticotropin releasing factor (CRF) family of peptides. CRF peptides have been shown to affect cardiovascular physiology. The effects of the peptides on cardioprotection after hypoxia/reoxygenation injury and on hypertrophy were examined. As SCP and SRP have a higher affinity for the CRF receptor 2 3, the only CRF receptor expressed in the rat heart, compared to UCN that additionally binds to the CRF receptor 1, the hypothesis was posed that the actions of SCP and SRP on cardiomyocytes will be more pronounced and more specific than UCN. As the pathways that are downstream of CRF receptors are not fully characterised, a possible mechanism of action is examined. The protective effect of the three peptides was compared and it was shown that all three are protective. Moreover, SCP and SRP are induced by hypoxia/reoxygenation injury. Examining the hypertrophic effects of the peptides it was concluded that all three exhibited such properties with SCP being the most potent. Furthermore, it is shown that UCN homologues require activation of MAPK p42/44 and PKB/Akt for their cardioprotective effects, but only PKB/Akt for hypertrophy. The involvement of two other important signalling molecules, iPLA2 and protein kinase Ce (PKCe) was also examined. iPLA2 protein levels are down-regulated by UCN peptides, - attenuating the effects of the enzyme after hypoxia/reoxygenation. PKCe protein levels are induced by UCN peptides indicating that PKCe is involved in the action of the peptides. Finally, UCN peptides upregulate the Sensitive to Apoptosis Gene (SAG) and the Katp channel, Kir 6.1 and these are two of the downstream effectors of cardioprotection. In addition, SAG appears to be a cardioprotective molecule that interacts with caspase-3. In conclusion, UCN peptides generate a multifaceted effect on cardiomyocyte physiology and we provide information on new mechanisms of action by the peptides. In addition, we illustrate that SCP is the most potent peptide of the three and provide additional evidence on the notion that C-terminal amidation of the CRF peptides is a requirement for their biological effect.

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