title: Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11betaHSD1-deficient mice post-MI.
abstract: OBJECTIVE
  Mice unable to locally regenerate corticosterone due to deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) have enhanced angiogenesis during acute myocardial infarct healing. The present study investigates the hypotheses that in these mice (i) inflammation and angiogenic signalling are promoted and (ii) longer-term remodelling and function are improved.
  
  
  RESULTS
  Myocardial infarction (MI) was induced by coronary artery ligation in 11βHSD1(-/-) and wild-type (C57BL/6) mice. Studies were terminated 2, 4, 7, and 28 days post-surgery. Increased vessel density (CD31 immunoreactivity) on the infarct border was confirmed 7 days after MI in 11βHSD1(-/-) hearts (P < 0.05) and was accompanied by improved ejection fraction (ultrasound) compared with C57BL/6. During wound healing, recruitment of neutrophils (at 2 days after MI) and macrophages (from 4 days after MI) and expression of monocyte-chemoattractant protein-1 was increased in 11βHSD1(-/-) compared with C57BL/6 hearts (P < 0.05). Recruitment of alternatively activated YM1-positive macrophages was particularly enhanced in the period preceding increased vessel density and was accompanied by increased expression of pro-angiogenic IL-8. By 28 days post-MI, when the infarct scar had matured, higher vessel density was maintained in 11βHSD1(-/-) hearts and vessels were smooth-muscle coated. Infarct scars were thicker (P < 0.001) in 11βHSD1(-/-) compared with C57BL/6 hearts and ejection fraction was higher (P < 0.05).
  
  
  CONCLUSIONS
  Increased vessel density in healing infarcts of mice deficient in 11(-/-)HSD1 follows recruitment of pro-reparative macrophages and increased pro-angiogenic signalling. Mature infarcts show less thinning and cardiac function is improved relative to wild-type mice, suggesting that 11βHSD1 may be a novel therapeutic target after MI.
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ Scotland, UK.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: McSweeney
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Kozak
authors.forename: Gary R
authors.initials: GR
authors.lastname: Small
authors.forename: Hiba
authors.initials: H
authors.lastname: Khaled
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Gray
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration; D013318:Stroke Volume; D013997:Time Factors; D016276:Ventricular Function; D014945:Wound Healing
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone