Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Purvis, Gareth S. D.; Chiazza, Fausto; Chen, Jianmin; Azevedo-Loiola, Rodrigo; Märtin, Lukas; Kusters, Dennis H. M.; Reutelingsperger, Chris; Fountoulakis, Nikolaos; Gnudi, Luigi; Yaqoob, M.; Collino, Massimo; Thiemermann, Christoph; Solito, Egle

doi:10.1007/s00125-017-4469-y

Cited by 47 publications

(72 citation statements)

References 51 publications

(82 reference statements)

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“…AnxA1 is expressed in endothelial cells and vascular smooth muscle cells in the vasculature (Pan et al, 2016;Paravicini, Yogi, Mazur, & Touyz, 2009), where it exhibits anti-inflammatory properties (Pan et al, 2016). Levels of AnxA1 are elevated in individuals with T1D, and deficiency in AnxA1 exhibits a more severe diabetic phenotype in the heart and kidney, compared to diabetic wild-type mice (Purvis et al, 2018). In addition, the levels of AnxA1 are also elevated in patients with T2D, and AnxA1 deficiency mice fed a high-fat diet (HFD) exhibt a more severe diabetic phenotype, including dyslipidaemia, insulin resistance (Purvis et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Jelinic

Kahlberg

Leo

et al. 2020

British J Pharmacology

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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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Section: Introductionmentioning

confidence: 99%

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Jelinic

Kahlberg

Leo

et al. 2020

British J Pharmacology

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“…Interventions that target cardiac inflammation may ultimately limit progression to heart failure and death in diabetes‐affected patients. One strategy involves the targeting of Annexin A1 (ANXA1), an endogenous glucocorticoid‐regulated anti‐inflammatory molecule that limits and resolves inflammation 135. ANX‐A1 binds to and activates the family of formyl peptide receptors (G protein‐coupled receptor family) to inhibit neutrophil activation, migration and infiltration.…”

Section: Diabetic Cardiomyopathy Antioxidant Defences and Immunothermentioning

confidence: 99%

“…ANX‐A1 binds to and activates the family of formyl peptide receptors (G protein‐coupled receptor family) to inhibit neutrophil activation, migration and infiltration. The physiological importance of this molecule was demonstrated in diabetic ANXA1 knockout mice who exhibit a worse diabetic phenotype and develop more severe cardiac dysfunction 135. Interestingly, plasma levels of ANXA1 were recently shown to be elevated in individuals with type 1 diabetes, with and without nephropathy compared with healthy individuals, and hypothesised to be elevated as a compensatory mechanism to protect tissues from the deleterious effects of hyperglycaemia 135.…”

Section: Diabetic Cardiomyopathy Antioxidant Defences and Immunothermentioning

confidence: 99%

“…The physiological importance of this molecule was demonstrated in diabetic ANXA1 knockout mice who exhibit a worse diabetic phenotype and develop more severe cardiac dysfunction 135. Interestingly, plasma levels of ANXA1 were recently shown to be elevated in individuals with type 1 diabetes, with and without nephropathy compared with healthy individuals, and hypothesised to be elevated as a compensatory mechanism to protect tissues from the deleterious effects of hyperglycaemia 135. More recent studies have shown that targeting ANXA1 to increase its expression can protect the diabetic heart from inflammatory injury.…”

Section: Diabetic Cardiomyopathy Antioxidant Defences and Immunothermentioning

confidence: 99%

“…More recent studies have shown that targeting ANXA1 to increase its expression can protect the diabetic heart from inflammatory injury. Indeed, administration of human recombinant ANXA1 halted further decline in cardiac function in diabetic mice via a pathway that included the restoration of Akt signalling 135. Targeting strategies have additionally included the use of ANXA1 peptides136 and small‐molecule‐biased formyl peptide receptor agonists to protect against myocardial injury 137.…”

Section: Diabetic Cardiomyopathy Antioxidant Defences and Immunothermentioning

confidence: 99%

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Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

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Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

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Multiple‐microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy

Liu

Yang

et al. 2019

Journal Cellular Physiology

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Diabetic nephropathy (DN) is a primary cause of renal failure. However, studies providing renal gene expression profiles of diabetic tubulointerstitial injury are scarce and its molecular mechanisms still await clarification. To identify vital genes involved in the diabetic tubulointerstitial injury, three microarray data sets from gene expression omnibus (GEO) were downloaded. A total of 127 differentially expressed genes (DEGs) were identified by limma package. Gene set enrichment analysis (GSEA) plots showed that sister chromatid cohesion was the most significant enriched gene set positively correlated with the DN group while retinoid X receptor binding was the most significant enriched gene set positively correlated with the control group. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included extracellular matrix organization, extracellular space, extracellular matrix structural constituent, and Staphylococcus aureus infection. Twenty hub genes from three significant modules were ascertained by Cytoscape. Correlation analysis and subgroup analysis between hub genes and clinical features of DN showed that ALB, ANXA1, APOH, C3, CCL19, COL1A2, COL3A1, COL4A1, COL6A3, CXCL6, DCN, EGF, HRG, KNG1, LUM, SERPINA3, SPARC, SRGN, and TIMP1 may involve in diabetic tubulointerstitial injury. ConnectivityMap analysis indicated the most significant three compounds are 5182598, thapsigargin and 5224221. In conclusion, this study may provide new insights into the molecular mechanisms underlying diabetic tubulointerstitial injury as well as potential targets for diagnosis and therapeutics of DN.

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Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Cited by 47 publications

References 51 publications

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

Multiple‐microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy

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