title: Cardiovascular effects of a PEGylated apelin.
abstract: Several studies have documented cardiovascular effects of apelin, including enhanced inotropy and vasodilation. However, these cardiovascular effects are short lived due to the predicted short circulating half-life of the apelin peptide. To address this limitation of apelin, we pursued N-terminal PEGylation of apelin and examined the cardiovascular effects of the PEGylated apelin. A 40kDa PEG conjugated apelin-36 (PEG-apelin-36) was successfully produced with N-terminal conjugation, high purity (>98%) and minimum reduction of APJ receptor binding affinity. Using an adenylate cyclase inhibition assay, comparable in vitro bioactivity was observed between the PEG-apelin-36 and unmodified apelin-36. In vivo evaluation of the PEG-apelin-36 was performed in normal rats and rats with myocardial infarction (MI). Cardiac function was assessed via echocardiography before, during a 20 min IV infusion and up to 100 min post peptide infusion. Similar increases in cardiac ejection fraction (EF) were observed during the infusion of PEG-apelin-36 and apelin-36 in normal rats. However, animals that received PEG-apelin-36 maintained significantly increased EF over the 100 min post infusion monitoring period compared to the animals that received unmodified apelin-36. Interestingly, EF increases observed with PEG-apelin-36 and apelin-36 were greater in the MI rats. PEG-apelin-36 had a prolonged circulating life compared to apelin-36 in rats. There were no changes in aortic blood pressure when PEG-apelin-36 or apelin-36 was administered. To our knowledge this is the first report of apelin PEGylation and documentation of its cardiovascular effects.
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701-9322, United States.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Jia
authors.forename: L
authors.initials: L
authors.lastname: Hou
authors.forename: A
authors.initials: A
authors.lastname: Leger
authors.forename: I
authors.initials: I
authors.lastname: Wu
authors.forename: A B
authors.initials: AB
authors.lastname: Kudej
authors.forename: J
authors.initials: J
authors.lastname: Stefano
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.forename: C Q
authors.initials: CQ
authors.lastname: Pan
authors.forename: G Y
authors.initials: GY
authors.lastname: Akita
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D062186:Arterial Pressure / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002460:Cell Line; D004452:Echocardiography; D005260:Female; D006207:Half-Life; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D011092:Polyethylene Glycols