Abstract 16031: The Apolipoprotein A1 Mimetic 4F Attenuates Cardiac Remodeling After Reperfused Infarction by Modulating Monocyte Polarity and Attenuating Immune Cell Activation
Heart failure (HF) is characterized by exaggerated systemic and myocardial pro-inflammatory responses, which impede myocardial healing and promote pathological remodeling and dysfunction. Currently, there are no strategies available to restrain and/or modulate immune cell responses triggered by myocardial injury. 4F, an apolipoprotein A-I mimetic, exhibits anti-inflammatory properties and influences macrophage polarity. We hypothesized that 4F treatment following reperfused myocardial infarction (MI) in mice would attenuate post-MI cardiac remodeling by inducing an anti-inflammatory and tissue healing monocyte polarity. C57BL/6 mice (6-8/group) were intravenously injected with either PBS or L-4F (100 μg/day) for 5 d starting at day 3 after reperfused MI (60 min ischemia). Flow cytometry revealed that compared to PBS injected MI mice, 4F significantly (p < 0.05) decreased levels of pro-inflammatory monocytes (CD45+Cd11b+Ly6Chigh) in blood (20.4 ± 4.6 vs 9.4 ± 1.7%), spleen (25.5 ± 7.4 vs 8.0 ± 6.0%), and heart (0.9 ± 0.4 vs 0.2 ± 0.1%); and decreased myocardial macrophage (CD45+CD11b+F4/80+) infiltration (1.6 ± 0.8 vs 0.28 ± 0.2%). The levels of anti-inflammatory monocytes, however, were unchanged. Echocardiography revealed that these changes in immune cell profiles in 4F-injected mice were also accompanied by improvements in cardiac function. Compared to PBS injected MI mice, 4F treatment attenuated post-MI LV chamber dilatation (84.1 ± 16 vs 65.0 ± 8.5 uL and 59.15 ± 16.6 vs 38.4 ± 11.8 uL; end-diastolic and systolic volumes, respectively), and improved LV ejection fraction (28.4 ± 10.8 vs 41.7 ± 12.8%). In addition, in vitro studies using mouse peritoneal macrophages indicated that 4F promotes an anti-inflammatory macrophage phenotype potentially by inhibiting the glycolytic metabolic profile typical of pro-inflammatory macrophages. These effects on macrophage polarity by 4F were associated with parallel alterations in the expression of hypoxia inducible factor isoforms 1 and 2α, known markers of macrophage polarity. We conclude that 4F could be used therapeutically after MI to augment reparative immune responses and thereby limit the long-term maladaptive effects of exaggerated inflammation on adverse post-MI cardiac remodeling.
Author Disclosures: T. Hamid: None. M.A. Ismahil: None. S.S. Bansal: None. B. Patel: None. M. Goel: None. A.M. Michaud: None. C.R. White: None. G.M. Anantharamaiah: None. S.D. Prabhu: None.
- © 2015 by American Heart Association, Inc.