Abstract
Preconditioning of the myocardium rapidly induces a number of transcription factors, which are likely to be responsible for a cascade of transcriptional changes underlying the development of delayed adaptation. Identifying these changes provides insight into the molecular pathways elicited by sub-lethal ischaemia and the mechanism leading to delayed adaptation. Genes up-regulated in rabbit myocardium in vivo by ischaemic preconditioning following reperfusion for 2 h, 4 h and 6 h post-treatment were identified by representational difference analysis of cDNA (cDNA. RDA). The area of the left ventricle rendered ischaemic by preconditioning or the equivalent area of sham-treated animals was isolated and cDNA.RDA performed. Three novel genes and six genes with known function where identified, including the TGFbeta receptor interacting protein 1, the alpha isoform of the A subunit of PP2 and the cap binding protein NCBP1. To determine whether expression of these genes correlated with preconditioning per se, expression was measured in myocardium after both ischaemic as well as heat shock induced preconditioning following 2 h, 4 h, and 6 h reperfusion. These genes were induced in rabbit myocardium in vivo by both ischaemia and heat shock, consistent with a fundamental role in the development of delayed adaptation. The well described role of PP2 in modulating the mitogen-activated protein kinase pathway and promoting cell survival is consistent with our previous work, which identified the reperfusion injury salvage kinase pathway in mediating the protective effects of ischaemic preconditioning. Expression of Trip1 and Ncbp1 also implicates TGFbeta signalling pathways and RNA processing and transport in delayed adaptation to stress in the myocardium.
Highlights
In the myocardium, short periods of sublethal ischaemia induce tolerance to subsequent periods of acute ischaemia
The rabbit myocardium was preconditioned by occluding the artery four times for a period of five minutes, with a ten minute period of reperfusion between occlusions
Impairment of complex I (CI) function enhances production of reactive oxygen species (Barrientos and Moraes, 1999) and can lead to apoptosis. These results suggest that increased synthesis of NADH dehydrogenase mRNA during PC may compensate for inhibition of mRNA synthesis induced by acute ischaemia, providing protection against apoptosis resulting from mitochondrial dysfunction
Summary
Short periods of sublethal ischaemia induce tolerance to subsequent periods of acute ischaemia This preconditioning or adaptation of the myocardium is manifested at two different times (Kuzuya et al, 1993; Marber et al, 1993). The second period appears later around 24 h after preconditioning (Marber et al, 1993; Kuzuya et al, 1993) and lasts for an extended time (48-72 h; Baxter et al, 1997) As this late period of protection extends over several days and protects against a variety of ischaemic pathologies, including irreversible cell and tissue injury, myocardial stunning, vascular endothelial dysfunction and ventricular arrhythmia (Baxter and Yellon, 1998), it may offer an important target for pharmacological intervention. The immediate early genes, c-fos and members of the jun family
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