Ablation of angiotensin type 2 receptor prevents endothelial nitric oxide synthase glutathionylation and nitration in ischaemic abductor muscle of diabetic mice

Robillard, Stéphanie; Mercier, Clément; Breton, Valérie; Paquin-Veillette, Judith; Guay, Andréanne; Lizotte, Farah; Geraldes, Pedro

doi:10.1177/1479164119883978

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…We have previously demonstrated that crucial factors involved in the angiogenic processes, such as VEGF, are affected in diabetes ( 7 , 25 ). To determine and understand if apelin can improve endothelial function under a hyperglycemic milieu, we have evaluated its role on critical steps involved in blood vessel formation and compared its response to VEGF-A.…”

Section: Resultsmentioning

confidence: 99%

Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb

Robillard

Tran

Lachance

et al. 2023

Front. Cardiovasc. Med.

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IntroductionPeripheral arterial disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients. Unfortunately, previous clinical studies investigating therapeutic angiogenesis using the vascular endothelial growth factor (VEGF) have shown disappointing results in diabetic patients, which evokes the necessity for novel therapeutic agents. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment improves revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. This study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia.MethodsNondiabetic and diabetic mice underwent femoral artery ligation to induce limb ischemia. Diabetic mice were implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed with voluntary wheels. In vitro, bovine aortic endothelial cells (BAECs) were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation.Results and DiscussionFollowing limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure. Our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD.

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Section: Resultsmentioning

confidence: 99%

Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb

Robillard

Tran

Lachance

et al. 2023

Front. Cardiovasc. Med.

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show abstract

“…We have previously demonstrated that crucial factors involved in the angiogenic processes, such as VEGF, are affected in diabetes 7,25 . To evaluate and understand if apelin can improve endothelial function under a hyperglycemic milieu, we have evaluated its role on critical steps involved in blood vessel formation and compared its response to VEGF-A.…”

Section: Resultsmentioning

confidence: 99%

Apelin improves angiogenesis and blood flow reperfusion following lower limb ischemia in diabetic mice

Robillard

Tran

Brazeau

et al. 2023

Preprint

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Objective: Peripheral artery disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients caused by an insufficient angiogenic response. Unfortunately, therapeutic angiogenesis using growth factors, such as the vascular endothelial growth factor (VEGF), are ineffective in diabetic conditions due to diabetes-induced growth factor resistance. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment has been shown to improve revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. Thus, this study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia. Approach and Results: Nondiabetic and diabetic mice underwent femoral artery ligation to induce lower limb ischemia. A group of diabetic mice was implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed in individual cages with voluntary wheels. In vitro, BAECs were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation. Following limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure. Conclusion: Pyr-apelin-13 promoted endothelial cell function and angiogenesis in the ischemic limb despite diabetes and HG level exposure. Therefore, our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD.

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“…AGTR2 [68], MUC5AC [70] and ATP12A [84] are a potential targets for IPF therapy. CYP1A1 [85], HHIP (hedgehog interacting protein) [86], AGTR2 [87], CYP2A6 [88] and PCK1 [83] expression had been confirmed in diabetes mellitus. In the light of important roles in cells, these DEGs in IPF might represent potential prognostic, diagnostics biomarkers and/or therapeutic targets for IPF.…”

Section: Discussionmentioning

confidence: 99%

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analysis of DEGs were performed. Then, a protein protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst database was used to construct the targeted microRNAs (miRNAs) and transcription factors (TFs) of the hub genes. Finally receiver operating characteristic (ROC) curve analysis was used to validates the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8 and EFHC2 were selected. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.

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Ablation of angiotensin type 2 receptor prevents endothelial nitric oxide synthase glutathionylation and nitration in ischaemic abductor muscle of diabetic mice

Cited by 7 publications

References 32 publications

Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb

Apelin prevents diabetes-induced poor collateral vessel formation and blood flow reperfusion in ischemic limb

Apelin improves angiogenesis and blood flow reperfusion following lower limb ischemia in diabetic mice

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

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