CRH-like peptides protect cardiac myocytes from lethal ischaemic injury

Simulated ischaemia causes both necrotic and apoptotic death of primary cul tures of neonatal rat cardiac myocytes. Simulated ischaemia is associated w ith increased expression of urocortin mRNA and with the release of urocorti n peptide into the medium. Exogenous urocortin is more potent than corticot ropin releasing hormone (CRH) in protecting cardiac myocytes from necrotic and apoptotic death induced by ischaemia, and the cardioprotective effects of ischaemia-preconditioned media are abrogated by antagonists: to the CRH family of peptides. Simulated ischaemia increases cardiac myocyte expressio n of CCAAT enhancer binding (C/EBP) transcription factors, and of the p65 s ubunit of NF kappa B, and reporter activity of a construct incorporating a fragment of the urocortin promoter containing a C/EBP consensus site is als o enhanced by simulated ischaemia. The data suggest that ischaemia, acting partly through increased expression of C/EBP transactivators, increases exp ression of urocortin mRNA, which is rapidly translated to the mature form. The mature peptide:is rapidly released, and exerts autocrine/paracrine prot ective effects through the cardiac CRH-R2 receptor which preferentially bin ds urocortin. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.