New targets of urocortin mediated cardioprotection

The urocortin (Ucn) hormones Ucn1 and Ucn2 have previously been shown to confer significant protection from myocardial ischaemia/reperfusion (I/R) injury; however the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of urocortins which underpin their cardioprotective activity, microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of Ucn1 or Ucn2 before the onset of reperfusion resulted in differential regulation of 66 and 141 genes respectively, the majority of which have not been previously been described. Functional analysis demonstrated that urocortin regulated genes were involved in a wide range of biological responses, including cell death (e.g. XIAP), oxidative stress (e.g. Nrf1/Nfe2l1) and metabolism (e.g. AMPK). In addition, both Ucn1 and Ucn2 were found to modulate the expression of a host of genes involved in G-protein coupled receptor (GPCR) signalling including Rac2, Gnb1, AIP1, Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of corticotrophin releasing hormone (CRH) receptors. Moreover, several of these GPCR related genes have previously been shown to be involved in MAPK activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we show that both Ucn1 and Ucn2 significantly reduce free radical damage following myocardial infarction and comparison of the urocortin gene signatures with that of the antioxidant tempol revealed significant overlap. These data uncover novel gene expression changes induced by urocortins which will serve as platform to further understand their mechanism of action in normal physiology and cardioprotection.