Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro, but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX-A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo. Adult ANX-A1−/− mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24–48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX-A1−/− mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX-A1−/− mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX-A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo. Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.
Background and purpose
Arterial stiffness, a characteristic feature of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti‐inflammatory protein annexin‐A1 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin‐A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin‐A1 in diabetes‐induced remodelling of mouse mesenteric vasculature.
Experimental approach
Insulin‐resistance was induced in male mice (AnxA1+/+ and AnxA1‐/‐) with the combination of streptozotocin (55mg/kg i.p. x 3 days) with high fat diet (42% energy from fat) or citrate vehicle with normal chow diet (20‐weeks). Insulin‐deficiency was induced in a separate cohort of mice using a higher total streptozocin dose (55mg/kg i.p. x 5 days) on chow diet (16‐weeks). At study endpoint, mesenteric artery passive mechanics were assessed by pressure myography.
Key results
Insulin‐resistance induced significant outward remodelling but had no impact on passive stiffness. Interestingly, vascular stiffness was significantly increased in AnxA1‐/‐ mice when subjected to insulin‐resistance. In contrast, insulin‐deficiency induced outward remodelling and increased volume compliance in mesenteric arteries, regardless of genotype. In addition, the annexin‐A1 / formyl peptide receptor axis is upregulated in both insulin‐resistant and insulin‐deficient mice.
Conclusion and implications
Our study provided the first evidence that endogenous AnxA1 may play an important vasoprotective role in the context of insulin‐resistance. AnxA1‐based therapies may provide additional benefits over traditional anti‐inflammatory strategies for reducing vascular injury in diabetes.
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