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Identification of two phosphorylation sites essential for annexin A1 in blood-brain barrier protection after experimental intracerebral hemorrhage in rats.

ABSTRACT: Annexin A1 has been reported to exert a blood-brain barrier protection. This study was designed to examine the role of annexin A1 in intracerebral hemorrhage-induced blood-brain barrier dysfunction. A collagenase intracerebral hemorrhage model was performed in adult male Sprague Dawley rats. First, a possible relationship between annexin A1 and intracerebral hemorrhage pathology was confirmed by a loss of annexin A1 in the cerebrovascular endothelium and serum of intracerebral hemorrhage rats, and the rescue effects of i.v. administration of human recombinant annexin A1 in vivo and annexin A1 overexpression in vitro on the barrier function of brain microvascular endothelial cells exposed to intracerebral hemorrhage stimulus. Second, we found that intracerebral hemorrhage significantly increased the phosphorylation ratio of annexin A1 at the serine/threonine residues. Finally, based on site-specific mutagenesis, we identified two phosphorylation sites (a) annexin A1 phosphorylation at threonine 24 is required for its interaction with actin cytoskeleton, and (b) phosphorylation at serine27 is essential for annexin A1 secretion, both of which were essential for maintaining cytoskeleton integrity and paracellular permeability. In conclusion, annexin A1 prevents intracerebral hemorrhage-induced blood-brain barrier dysfunction in threonine 24 and serine27 phosphorylation-dependent manners. Annexin A1 phosphorylation may be a self-help strategy in brain microvascular endothelial cells after intracerebral hemorrhage; however, that was almost completely abolished by the intracerebral hemorrhage-induced loss of annexin A1.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5531348 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Identification of two phosphorylation sites essential for annexin A1 in blood-brain barrier protection after experimental intracerebral hemorrhage in rats.

Wang Zhong Z Chen Zhouqing Z Yang Junjie J Yang Ziying Z Yin Jia J Zuo Gang G Duan Xiaochun X Shen Haitao H Li Haiying H Chen Gang G

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 7

Annexin A1 has been reported to exert a blood-brain barrier protection. This study was designed to examine the role of annexin A1 in intracerebral hemorrhage-induced blood-brain barrier dysfunction. A collagenase intracerebral hemorrhage model was performed in adult male Sprague Dawley rats. First, a possible relationship between annexin A1 and intracerebral hemorrhage pathology was confirmed by a loss of annexin A1 in the cerebrovascular endothelium and serum of intracerebral hemorrhage rats, a ...[more]

PMID: 27634935

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Project description:Background and aimsThe apolipoprotein B (apoB)/apolipoprotein A1 (apoA1) ratio is a key indicator in predicting future cardiovascular outcomes. However, it is still unclear whether the ratio of apoB/apoA1 is a better predictor of the outcomes after intracerebral hemorrhage (ICH). Therefore, we aimed to assess the relationships between the ratio of apoB/apoA1 and functional outcomes, all-cause mortality, and stroke recurrence in ICH patients.MethodsTwo hundred and sixteen Chinese ICH patients participated in this study from December 2018 to December 2019. Laboratory routine tests including hematology analysis, coagulation tests, and lipid levels were examined. The clinical outcomes included functional outcomes evaluated by the modified Rankin Scale score (mRS), all-cause death, and stroke recurrence 1 year after discharge. Associations between the apoB/apoA1 ratio and the outcomes were evaluated using logistic regression analysis. Based on multivariate analysis, we constructed a nomogram. Univariate survival analysis was performed by the Kaplan-Meier method and log-rank test. All the patients were classified into two groups by the median value of the apoB/apoA1 ratio: B1 < 0.8 and B2 ≥ 0.8.ResultsOf the 216 patients, 107 had an apoB/apoA1 ratio ≥ 0.8. Eighty-five patients had poor functional outcomes (mRS ≥ 3), and 32 patients had severe functional outcomes (mRS ≥ 4). During the 1-year follow-up, a total of 18 patients died, and 13 patients had apoB/apoA1 ratio levels ≥0.8 during the 1-year follow-up period. Moreover, 16 recurrent strokes were recorded. Adjustments for age, sex, smoking, alcohol, body mass index, lipid levels, and hematoma site and volume showed that a high apoB/apoA1 ratio was significantly related to adverse functional outcomes and all-cause mortality. The ORs for B2 versus B1 were 3.76 (95% CI: 1.37 to 10.40, p = 0.010), 22.74 (95% CI: 1.08 to 474.65, p = 0.044), and 7.23 (95% CI: 1.28 to 40.88, p = 0.025) for poor functional outcomes with mRS ≥ 3, mRS ≥ 4, and all-cause mortality, respectively.ConclusionAn increased apoB/apoA1 ratio at admission was independently related to poor functional outcome and all-cause mortality in ICH patients at the 1-year follow-up.

Dataset Information

Identification of two phosphorylation sites essential for annexin A1 in blood-brain barrier protection after experimental intracerebral hemorrhage in rats.

Publications

Identification of two phosphorylation sites essential for annexin A1 in blood-brain barrier protection after experimental intracerebral hemorrhage in rats.

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