Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI

Mice unable to locally regenerate corticosterone due to deficiency of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) 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. Myocardial infarction (MI) was induced by coronary artery ligation in 11 beta HSD1(-/-) 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 11 beta HSD1(-/-) 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 11 beta HSD1(-/-) 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 11 beta HSD1(-/-) hearts and vessels were smooth-muscle coated. Infarct scars were thicker (P < 0.001) in 11 beta HSD1(-/-) compared with C57BL/6 hearts and ejection fraction was higher (P < 0.05). 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 11 beta HSD1 may be a novel therapeutic target after MI.