Abstract 3343: Sustained Enhancement of Cardiac Function Follows Increased Recruitment of Pro-angiogenic Macrophages to Healing Infarcts of 11 Beta Hydroxysteroid Dehydrogenase Type 1 Deficient Mice
Mice unable to locally regenerate corticosterone due to deficiency in 11 β hydroxysteroid dehydrogenase type 1 (11HSD1) have an enhanced angiogenic response during myocardial infarct (MI) healing. This study investigates the hypothesis that angiogenesis is prompted by enhanced recruitment of macrophages, particularly alternatively activated macrophages, that secrete pro-angiogenic cytokines. Male C57Bl6 (WT) and 11HSD1 deficient (KO) mice underwent coronary artery ligation for induction of MI, or sham-operation. Post-surgery cardiac function was assessed by echocardiography. Left ventricle (LV) was collected for immunohistochemical and molecular analysis. Neutrophil infiltration peaked 2 days after MI and was significantly enhanced in the 11HSD1 KO compared to WT mice (1.2±0.1 vs. 0.8±0.1 cells/40μm2 P<0.05, n=4 –12), despite comparable infarct size in both groups. Increased LV macrophage accumulation in KO was shown by enhanced Mac 2 immunoreactivity at 7 days (27.4±3.1 vs. 16.3±2.5%, P<0.01) and confirmed by flow cytometry. Moreover, in the KO a greater proportion of macrophages were of the alternatively activated, YM1 positive, phenotype (P<0.001). LV expression of pro-angiogenic IL-8, but not VEGF, was increased. Cellular proliferation (511.0±175.9 vs 196.5±37.2 BrdU incorporating cells/mm2 P<0.01) and vessel density (1.8±0.2 vs 1.3±0.1 CD31 positive vessels per 400μm2 P<0.05) at 7 days were greater in KO compared to WT LV. At 28 days after MI, CD31 vessel density on the infarct border remained elevated in KO compared to WT. Vessel maturation was suggested by the parallel increase in αsmooth muscle actin positive vessels. LV ejection fraction was decreased after MI, but was significantly increased in KO compared to WT at 7 (P<0.05) and 28 days after MI (41.6±3.8 vs 26.7±3.8% P<0.01). Scar thickness was greater in the KO than the WT 28 days post MI (P<0.001) and there was a trend for decreased scar length (36.3±3.0 vs. 42.6±3.0% of LV, n=10). Deficiency of 11HSD1 results in reduced scar thinning and sustained improvement of cardiac function post-MI. Promotion of angiogenesis secondary to enhanced recruitment of pro-angiogenic macrophages may contribute to the cardioprotection associated with intracellular glucocorticoid deficiency.