216 Immediate Pharmacological Inhibition of Local Glucocorticoid Generation increases Angiogenesis and Improves Cardiac Funcion after Myocardial Infarction

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Mice lacking the glucocorticoid regenerating enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), responsible for local regeneration of corticosterone, have increased peri-infarct angiogenesis (Small et al ., 2005) and improved cardiac function (McSweeney et al ., 2010) following myocardial infarction (MI). The aim of the present study was to investigate whether these beneficial outcomes could be reproduced by a pharmacological inhibitor of 11βHSD1, UE2316.

MI was induced in 45 male C57Bl6 mice by coronary artery ligation. UE2316 (10 mg/kg/day) or vehicle was administered by osmotic minipump implanted at the time of MI induction. Cardiac function was assessed by high resolution ultrasound at 7 days and 21 days after MI after which tissue was collected for assessment of infarct area (Massons trichrome) and blood vessel density (vessels immunopositive for CD31). An additional group of mice UE2316 was administered orally for 2 weeks prior to MI, followed by implantation of mini-pump as above.

Treatment with UE2316 did not result in any alteration in plasma concentration of troponin I at 24 h after MI. However, by 3 weeks after induction of MI ejection fraction (EF) was reduced from 72 ± 5% to 30 ± 3% in vehicle treated animals, but in mice that that received UE2316 from the time of MI, EF was significantly increased to 43 ± 5 mmHg (P < 0.05). Additional treatment prior to induction of MI did not cause a further improvement in EF (43 ± 10%). 7 days after induction of MI, vascular density was increased in the infarct and peri-infarct zone in UE2316 compared to vehicle treated mice (P < 0.05) and this was associated with a reduction in infarct area from from 35 ± 7% LV in vehicle group, to 20 ± 2% LV in U12316 group.

These data demonstrate that the beneficial effects of 11βHSD1 genetic deletion can be recapitulated by pharmacological inhibition of this enzyme. Importantly, reduction of infarct size and enhancement of ejection fraction can be achieved by delivery of drug at the time of infarction, supporting potential therapeutic utility of this intervention.

This study was supported by the Wellcome Trust (PG-WT091720) and by a BHF Centre of Research Excellence Award.


Small GR, et al. Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. PNAS 2005;102:12165–12170


McSweeney S, et al. Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI. Cardiovasc Res. 2010;88:159–167

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