title: The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo.
abstract: OBJECTIVE
  The endogenous peptide apelin is differentially regulated in cardiovascular disease but the nature of its role in cardiac function remains unclear.
  
  
  METHODS
  We investigated the functional relevance of this peptide using ECG and respiration gated magnetic resonance imaging, conductance catheter pressure-volume hemodynamic measurements, and echocardiography in vivo. In addition, we carried out histology and immunohistochemistry to assess cardiac hypertrophy and to localize apelin and APJ in the adult and embryonic mouse heart.
  
  
  RESULTS
  Intraperitoneal injection of apelin (300 microg/kg) resulted in a decrease in left ventricular end diastolic area (pre: 0.122+/-0.007; post: 0.104+/-0.005 cm(2), p=0.006) and an increase in heart rate (pre: 537+/-20; post: 559+/-19 beats per minute, p=0.03). Hemodynamic measurements revealed a marked increase in ventricular elastance (pre: 3.7+/-0.9; post: 6.5+/-1.4 mm Hg/RVU, p=0.018) and preload recruitable stroke work (pre: 27.4+/-8.0; post: 51.8+/-3.1, p=0.059) with little change in diastolic parameters following acute infusion of apelin. Chronic infusion (2 mg/kg/day) resulted in significant increases in the velocity of circumferential shortening (baseline: 5.36+/-0.401; 14 days: 6.85+/-0.358 circ/s, p=0.049) and cardiac output (baseline: 0.142+/-0.019; 14 days: 0.25+/-0.019 l/min, p=0.001) as determined by 15 MHz echocardiography. Post-mortem corrected heart weights were not different between apelin and saline groups (p=0.5) and histology revealed no evidence of cellular hypertrophy in the apelin group (nuclei per unit area, p=0.9). Immunohistochemistry studies revealed APJ staining of myocardial cells in all regions of the adult mouse heart. Antibody staining, as well as quantitative real time polymerase chain reaction identified expression of both APJ and apelin in embryonic myocardium as early as embryonic day 13.5.
  
  
  CONCLUSIONS
  Apelin reduces left ventricular preload and afterload and increases contractile reserve without evidence of hypertrophy. These results associate apelin with a positive hemodynamic profile and suggest it as an attractive target for pharmacotherapy in the setting of heart failure.
authors.affiliation: Donald W. Reynolds Cardiovascular Research Center, Division of Cardiovascular Medicine, Stanford University, Stanford, CA 94305, USA. euan@stanford.edu
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Powers
authors.forename: Mary
authors.initials: M
authors.lastname: Chen
authors.forename: Ramendra
authors.initials: R
authors.lastname: Kundu
authors.forename: Tom
authors.initials: T
authors.lastname: Finsterbach
authors.forename: Anthony
authors.initials: A
authors.lastname: Caffarelli
authors.forename: Alicia
authors.initials: A
authors.lastname: Deng
authors.forename: Jens
authors.initials: J
authors.lastname: Eichhorn
authors.forename: Raina
authors.initials: R
authors.lastname: Mahajan
authors.forename: Rani
authors.initials: R
authors.lastname: Agrawal
authors.forename: Joan
authors.initials: J
authors.lastname: Greve
authors.forename: Robert
authors.initials: R
authors.lastname: Robbins
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Patterson
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000032:analysis / Q000494:pharmacology*; D006321:Heart / Q000196:embryology / Q000503:physiopathology; D006439:Hemodynamics; D007150:Immunohistochemistry / Q000379:methods; D015918:Infusion Pumps, Implantable; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled