title: Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis.
abstract: Promoting angiogenesis is a key therapeutic target for protection from chronic ischemic cardiac injury. Endothelial-Monocyte-Activating-Polypeptide-II (EMAP II) protein, a tumor-derived cytokine having anti-angiogenic properties in cancer, is markedly elevated following myocardial ischemia. We examined whether neutralization of EMAP II induces angiogenesis and has beneficial effects on myocardial function and structure after chronic myocardial infarction (MI). EMAP II antibody (EMAP II AB), vehicle, or non-specific IgG (IgG) was injected ip at 30 min and 3, 6, and 9 days after permanent coronary artery occlusion in mice. EMAP II AB, compared with vehicle or non-specific antibody, significantly, p<0.05, improved the survival rate after MI, reduced scar size and attenuated the development of heart failure, i.e., left ventricular ejection fraction was significantly higher in EMAP II AB group, fibrosis was reduced by 24%, and importantly, more myocytes were alive in EMAP II AB group in the infarct area. In support of an angiogenic mechanism, capillary density (193/HPF vs. 172/HPF), doubling of the number of proliferating endothelial cells, and angiogenesis related biomarkers were upregulated in mice receiving EMAP II AB treatment as compared to IgG. Furthermore, EMAP II AB prevented EMAP II protein inhibition of in vitro tube formation in HUVECs. We conclude that blockade of EMAP II induces angiogenesis and improves cardiac function following chronic MI, resulting in reduced myocardial fibrosis and scar formation and increased capillary density and preserved viable myocytes in the infarct area.
authors.affiliation: Department of Cell Biology & Molecular Medicine, The Cardiovascular Research Institute at Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Chujun
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Cell Biology & Molecular Medicine, The Cardiovascular Research Institute at Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Cell Biology & Molecular Medicine, The Cardiovascular Research Institute at Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Solanki
authors.affiliation: Department of Cell Biology & Molecular Medicine, The Cardiovascular Research Institute at Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.affiliation: Department of Medicine, The Cardiovascular Research Institute at Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: vatnerdo@njms.rutgers.edu.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, South Bend, IN 46617, USA. Electronic address: schwarma@iu.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D016019:Survival Analysis; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000906:Antibodies; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1
keywords: Angiogenesis; Cardioprotection; EMAP II inhibition; Myocardial infarction