Formyl-peptide receptor is not involved in the protection afforded by annexin 1 in murine acute myocardial infarct.
Recent interest in the annexin 1 field has come from the notion that specific G-protein-coupled receptors, members of the formyl-peptide receptor (FPR) family, appear to mediate the anti-inflammatory actions of this endogenous mediator. Administration of the annexin 1 N-terminal derived peptide Ac2-26 to mice after 25 min ischemia significantly attenuated the extent of acute myocardial injury as assessed 60 min postreperfusion. Evident at the dose of 1 mg/kg (approximately 9 nmol per animal), peptide Ac2-26 cardioprotection was intact in FPR null mice. Similarly, peptide Ac2-26 inhibition of specific markers of heart injury (specifically myeloperoxidase activity, CXC chemokine KC contents, and endogenous annexin 1 protein expression) was virtually identical in heart samples collected from wild-type and FPR null mice. Mouse myocardium expressed the mRNA for FPR and the structurally related lipoxin A4 receptor, termed ALX; thus, comparable equimolar doses of two ALX agonists (W peptide and a stable lipoxin A4 analog) exerted cardioprotection in wild-type and FPR null mice to an equal extent. Curiously, marked (>95%) blood neutropenia produced by an anti-mouse neutrophil serum did not modify the extent of acute heart injury, whereas it prevented the protection afforded by peptide Ac2-26. Thus, this study sheds light on the receptor mechanism(s) mediating annexin 1-induced cardioprotection and shows a pivotal role for ALX and circulating neutrophil, whereas it excludes any functional involvement of mouse FPR. These mechanistic data can help in developing novel therapeutics for acute cardioprotection.
Gavins
Felicity N E
FN
Centre of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London, UK.
Kamal
Ahmad M
AM
D'Amico
Michele
M
Oliani
Sonia M
SM
Perretti
Mauro
M
D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000502:physiology*; D015415:Biomarkers; D002316:Cardiotonic Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury; D009504:Neutrophils / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D017305:Annexin A1; D015415:Biomarkers; D002316:Cardiotonic Agents; C469988:Fpr1 protein, mouse; D010455:Peptides; D044042:Receptors, Formyl Peptide