title: Elastase-2, an angiotensin II-generating enzyme, contributes to increased angiotensin II in resistance arteries of mice with myocardial infarction.
abstract: Angiotensin II (Ang II), whose generation largely depends on angiotensin-converting enzyme (ACE) activity, mediates most of the renin-angiotensin-system (RAS) effects. Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved in Ang II-generation in resistance arteries are unknown. We hypothesized that ELA-2 contributes to vascular Ang II generation and cardiac damage in mice subjected to MI.
  
  
  
  Concentration-effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA-2 knockout (ELA-2KO) mice subjected to left anterior descending coronary artery ligation (MI).
  
  
  
  MI size was similar in WT and ELA-2KO mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA-2KO mice. Ang I-induced contractions increased in WT mice subjected to MI (MI-WT) compared with sham-WT mice. No differences were observed in Ang I reactivity between arteries from ELA-2KO and ELA-2KO subjected to MI (MI-ELA-2KO). Ang I contractions increased in arteries from MI-WT versus MI-ELA-2KO mice. Chymostatin attenuated Ang I-induced vascular contractions in WT mice, but did not affect Ang I responses in ELA-2KO arteries.
  
  
  
  These results provide the first evidence that ELA-2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA-2 as a key player in ACE-independent dysregulation of the RAS.
authors.affiliation: Departments of Pharmacology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.|Physiology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.|Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Becari
authors.affiliation: Departments of Pharmacology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Marcondes A B
authors.initials: MAB
authors.lastname: Silva
authors.affiliation: Physiology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.|Department of Medicine, University of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
authors.forename: Marina T
authors.initials: MT
authors.lastname: Durand
authors.affiliation: Pathology and Legal Medicine, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Cibele M
authors.initials: CM
authors.lastname: Prado
authors.affiliation: Biochemistry and Immunology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Eduardo B
authors.initials: EB
authors.lastname: Oliveira
authors.affiliation: Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Mauricio S
authors.initials: MS
authors.lastname: Ribeiro
authors.affiliation: Physiology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Helio C
authors.initials: HC
authors.lastname: Salgado
authors.affiliation: Departments of Pharmacology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Maria Cristina O
authors.initials: MCO
authors.lastname: Salgado
authors.affiliation: Departments of Pharmacology, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism / Q000601:surgery; D008026:Ligation; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; D012697:Serine Endopeptidases; C117309:pancreatic elastase II