Abstract 14785: Endogenous Annexin-A1 Regulates Hematopoietic Stem Cell Mobilization Post Myocardial Infarction in Mice in vivo
Introduction: Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important protective role in preserving left ventricular (LV) viability and function after ischemic insults in vitro but its longer-term cardioprotective actions in vivo are largely unknown.
Hypothesis: We tested the hypothesis that ANX-A1 deficiency exaggerates inflammation, hematopoietic stem progenitor cell (HSPC) activity and LV remodeling in response to myocardial ischemia in mice in vivo.
Methods and Results: Adult ANX-A1-/- mice subjected to coronary artery occlusion with 24h reperfusion exhibit increased infarct size (49.3±5.4 vs. 34.8±1.7%, P<0.05, n=8-9) compared to ANX-A1+/+ mice. LV macrophage content after 48h reperfusion is significantly increased (873±86 vs. 546±71 macrophages/mm2). Eight days post-myocardial infarction (MI), ANX-A1-/- mice exhibit greater expansion and altered mobilization of HSPCs, with increased circulating neutrophil and platelet numbers. As HSPCs are inflammatory cell precursors and play important roles in MI inflammatory responses, these observations are consistent with increased cardiac inflammation as a result of increased myeloid cells entering injured myocardium. MI upregulates LV ANP expression 2-fold in ANX-A1+/+ mice (P<0.05 vs sham) and tends to further increase in ANX-A1-/- mice (P=0.08). This corresponds to exaggerated heart weight (7.3±0.4 vs 5.6±0.2mg/g; P<0.001) and LV weight (4.9±0.2 vs 4.2±1.2mg/g; P<0.05) relative to bodyweight, in ANX-A1-/- compared to ANX-A1+/+ mice. LV pro-inflammatory TNF-α and pro-fibrotic CTGF gene expression are increased 7-fold in ANX-A1-/- (compared to 2-fold in ANX-A1+/+) mice. This is accompanied by exaggerated LV collagen deposition, 8 days after MI (41±7 vs 19±2%), consistent with a larger infarct in ANX-A1-/- mice at this later stage.
Conclusions: ANX-A1-deficiency increases cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity. These findings suggest endogenous ANX-A1 regulates HSPC mobilisation and differentiation to limit monocyte/neutrophil production. As a consequence, endogenous ANX-A1 may limit LV damage in vivo. Development of novel ANX-A1 based therapies may hence improve outcomes after MI.
Author Disclosures: C. Qin: None. S. Finlayson: None. A. AI-Sharea: None. S. Rosli: None. M.J. De Blasio: None. C.J. Thomas: None. H. Kiriazis: None. Y.H. Yang: None. E.F. Morand: None. A.J. Murphy: None. X. Du: None. X. Gao: None. R.H. Ritchie: None.
- © 2016 by American Heart Association, Inc.