A critical cytoprotective role of endogenous adrenomedullin in acute myocardial infarction.
Exogenous administration or transfection of adrenomedullin (AM) affords protection against ischaemia-reperfusion injury. Here we have examined the role of endogenous AM in regulating the development of myocardial infarction. Wild type (WT) and AM(+/-) mice underwent 30 min regional myocardial ischaemia and 120 min reperfusion. In AM(+/-) hearts, tetrazolium-determined infarct size was greater than in WT controls (27.9 +/- 2.0 vs. 17.7 +/- 2.4%, P < 0.01) and mortality rate was increased (35% vs. 14%, P < 0.05). Treatment with exogenous recombinant AM (200 ng/kg) prior to coronary occlusion rescued the ischaemia-reperfusion intolerant phenotype of AM(+/-) mice and further limited infarct development in WT mice. Administration of recombinant AM was associated with augmented phosphorylation of Akt and eNOS in early reperfusion suggesting a role for AM in regulating this survival pathway. These studies provide the first evidence that expression of AM is a critical factor regulating myocardial tolerance to ischaemia-reperfusion injury.
Hamid
Shabaz A
SA
Department of Basic Sciences, The Royal Veterinary College, University of London, UK. shamid@rvc.ac.uk
Baxter
Gary F
GF
D053607:Adrenomedullin; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D010455:Peptides; D011994:Recombinant Proteins; D053607:Adrenomedullin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051058:Oncogene Protein v-akt