Recombinant Annexin II Modulates Impaired Fibrinolytic Activity In Vitro and in Rat Carotid Artery

Ishii, Hiroko; Yoshida, Masayuki; Hiraoka, M; Hajjar, Katherine A.; Tanaka, Akira; Yasukochi, Yukio; Numano, Fujío

doi:10.1161/hh2401.101066

Cited by 52 publications

(65 citation statements)

References 24 publications

(17 reference statements)

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“…Interestingly, there were no significant differences in ADC lesion volume at 180 min after stroke among groups B, C and D. These results are consistent with our previous observation that rAN II-promoted plasmin generation may have been saturated at higher concentrations (Ishii et al, 2001). …”

Section: Discussionsupporting

confidence: 91%

“…We have previously shown that annexin 2 is attached to endothelial cells in a calcium-dependent manner and fibrinolytic activity disappears in the absence of calcium (Ishii et al, 2001). rAN II restored impaired fibrinolytic activity and sustained carotid flow when rAN II was present on the endothelium.…”

Section: Discussionmentioning

confidence: 92%

“…rAN II restored impaired fibrinolytic activity and sustained carotid flow when rAN II was present on the endothelium. Deletion of the C-terminal 224 amino acid results in a lost fibrinolytic activity of annexin 2 (Ishii et al, 2001), suggesting that C-terminal 224 amino acids in annexin 2 plays important in phospholipid binding to plasminogen. Moreover, rAN II inhibits the formation of thrombus and overexpressed annexin 2 protein on intima of rat carotid artery can be detected by fluorescent immunochemistry.…”

Section: Discussionmentioning

confidence: 99%

“…The method used to prepare rAN II was previously described in details (Ishii et al, 2001). Animals were treated with various doses of rAN II or saline in a blinded manner and investigated after embolization in rAN II-treated group, rAN II was administered intravenously less than 5 min before the induction of embolic stroke.…”

Section: Recombinant Annexin 2 Administrationmentioning

confidence: 99%

“…Intravenous administration of recombinant annexin 2 (rAN II) significantly inhibits thrombus formation in vivo without affecting fibrinolytic and coagulation parameters in a rat carotid artery model (Ishii et al, 2001), suggesting rAN II could potentially be used in antithrombolytic treatment of stroke with minimal side effects.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

et al. 2007

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Efficacy of recombinant annexin 2 (rAN II) in a rat model of embolic stroke was examined using a magnetic resonance imaging (MRI) and histology. The right middle cerebral artery of male Wistar rats was occluded by autologous clots under anesthesia. Four doses of rAN II (0.125, 0.25, 0.5 and 1.0 mg/kg, n = 10 for each group) or saline (1 ml/kg, n = 10) were administrated intravenously within 5 min before clot infusion. Serial changes in apparent diffusion coefficient (ADC) and relative blood flow (CBF) were measured with the use of MRI in half of the animals in each group. The remaining half of the animals in each group was evaluated for hemorrhage and final infarct size by histology at 48 h after embolization. At 3 h after embolization, lesion volumes with ADC were abnormality and CBF in the peripheral lesion was improved in groups treated with 0.25, 0.5 and 1.0 mg/kg, but not 0.125 mg/kg, of rAN II in comparison with the saline-treated group (P < 0.05). Histological analyses were consistent with MRI findings. More importantly, no hemorrhagic transformation was documented in rats treated with 0.125 and 0.25 mg/kg of rAN II, whereas it was observed at higher doses. We concluded that rAN II at 0.25 mg/kg significantly reduced infarct size and improved CBF without hemorrhagic complications. rAN II is a novel compound that has the potential to be a promising fibrinolytic agent to treat embolic stroke.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Recombinant Annexin 2 Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

et al. 2007

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RETRACTED: Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2

Belvedere

Morretta

Pessolano

et al. 2020

Journal Cellular Physiology

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Mesoglycan is a drug based on a mixture of glycosaminoglycans mainly used for the treatment of blood vessel diseases acting as antithrombotic and profibrinolytic drugs. Besides the numerous clinical studies, there is no information about its function on the fibrinolytic cascade. Here, we have elucidated the mechanism of action by which mesoglycan induces the activation of plasmin from endothelial cells. Surprisingly, by a proteomic analysis, we found that, following mesoglycan treatment, these cells show a notable amount of annexin A2 (ANXA2) at the plasma membrane. This protein has been widely associated with fibrinolysis and appears able to move to the membrane when phosphorylated. In our model, this translocation has proven to enhance cell migration, invasion, and angiogenesis. Furthermore, the interaction of mesoglycan with syndecan 4 (SDC4), a coreceptor belonging to the class of heparan sulfate proteoglycans, represents the upstream event of the ANXA2 behavior. Indeed, the activation of SDC4 triggers the motility of endothelial cells culminating in angiogenesis. Interestingly, mesoglycan can induce the release of plasmin in endothelial cell supernatants only in the presence of ANXA2. This evaluation suggests that mesoglycan triggers the formation of a chain mechanism starting from the activation of SDC4, and the related cascade of events, including src complex and PKCα activation, promoting the phosphorylation of ANXA2 and its translocation to plasma membrane. This indicates a connection among mesoglycan, SDC4‐(PKCα‐src), and ANXA2 which, in turn, links the tissue plasminogen activator bringing it closer to plasminogen. This latter is so cleaved to release the plasmin and degrade fibrin sleeves.

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Atorvastatin modifies the protein profile of circulating human monocytes after an acute coronary syndrome

Barderas¹,

Tuñón²,

Dardé³

et al. 2009

Proteomics

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Aggressive treatment with high-dose atorvastatin reduces more effectively the incidence of cardiovascular events than moderate statin therapy. The mechanism of this benefit has not been fully elucidated. In order to know the potential effects of statin treatment on the protein expression of circulating monocytes in acute coronary syndrome (ACS) patients, a proteomic analysis of these cells was carried out by 2-DE and MS. Twenty-five patients with non-ST-elevation acute coronary syndrome (NSTEACS) were randomized, the fourth day after admission, to receive ATV 80 mg/dL (n = 14) or conventional treatment (CT) (n = 11), for two months. Blood was withdrawn at the end of the treatment, and monocytes were extracted for proteomic analysis and their protein expression patterns determined. Age, sex, total cholesterol, LDL, HDL, triglycerides, body mass index, presence of hypertension, diabetes, and smoking status were not significantly different between the two groups of patients. The expression of 20 proteins was modified by intensive ATV. Among the most relevant results stand out the normalization by intensive ATV treatment of the expression of proteins that modulate inflammation and thrombosis such as protein disulfide isomerase ER60 (PDI), Annexin I, and prohibitin, or that have other protective effects as HSP-70. Thus, this approach shed light at the molecular level of the beneficial mechanisms of anti-atherothrombotic drugs.

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Recombinant Annexin II Modulates Impaired Fibrinolytic Activity In Vitro and in Rat Carotid Artery

Cited by 52 publications

References 24 publications

Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

RETRACTED: Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2

Atorvastatin modifies the protein profile of circulating human monocytes after an acute coronary syndrome

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