Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment

Sun, Yu; Lee, Jolly; Huang, Henry; Wagner, Mary B.; Joiner, Clinton H.; Archer, David; Kuan, Chia-Yi

doi:10.1161/strokeaha.117.018334

Cited by 13 publications

(23 citation statements)

References 32 publications

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“…The humanized knock‐in sickle cell mice utilized in this study provides an excellent model of SCD that recapitulates all the major features of sickle cell pathology in humans (Wu et al , ; Hyacinth et al , ; Sun et al , ). The experimental and control groups of mice studied in this experiment were similar at baseline.…”

Section: Discussionmentioning

confidence: 99%

Renal protection by atorvastatin in a murine model of sickle cell nephropathy

et al. 2018

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Recent studies have demonstrated pleiotropic effects of statins in various mouse models of kidney disease. In this study, Townes humanized sickle cell mice were treated for 8 weeks with atorvastatin at a dose of 10 mg/kg/day starting at 10 weeks of age. Treatment with atorvastatin significantly reduced albuminuria, and improved both urine concentrating ability and glomerular filtration rate. Atorvastatin also decreased markers of kidney injury and endothelial activation, and ameliorated oxidant stress in renal tissues and peripheral macrophages. Atorvastatin downregulated the expression of mRNA levels of the NADPH oxidases, Cybb (also termed Nox2) and Nox4, which are major sources of oxidant stress in the kidney. These findings highlight the pleiotropic effects of atorvastatin and suggest that it may provide beneficial effects in sickle cell nephropathy.

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Section: Discussionmentioning

confidence: 99%

Renal protection by atorvastatin in a murine model of sickle cell nephropathy

et al. 2018

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“…Immunohistochemistry and immunoblotting were performed as previously described. [20][21][22] The antibodies were rabbit anti-fibrinogen (#MBS315814, MyBioSource), rat anti-TER119 (#14-59-2182, Invitrogen), rat anti-glycoprotein IIb (#553847, Becton Dickinson), Isolectin GS-IB4 (I21413, Invitrogen), and mouse anti-GAPDH (#G8795, Sigma).…”

Section: Immunohistochemistry and Immunoblotmentioning

confidence: 99%

A murine photothrombotic stroke model with an increased fibrin content and improved responses to tPA-lytic treatment

et al. 2020

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The Rose Bengal (RB) dye-based photothrombotic stroke (PTS) model has many methodological advantages including consistent location and size of infarct, low mortality, and relatively simple surgical procedures. However, the standard PTS has the caveat of poor responses to tissue-type plasminogen activator (tPA)–mediated lytic treatment, likely as a result of the platelet-rich, fibrin-poor content of the blood clots. Here we tested whether the admixture of thrombin (80 U/kg) and RB dye (50 mg/kg) in the proximal middle cerebral artery (MCA)–targeted PTS will modify the clot composition and elevate the responsiveness to tPA-lytic treatment (Alteplase, 10 mg/kg). Indeed, intravital imaging, immunostaining, and immunoblot analyses showed less-compacted platelet aggregates with a higher fibrin content in the modified thrombin (T) plus RB photothrombotic stroke (T+RB-PTS) model compared with the standard RB-PTS-induced clots. Both RB-PTS and T+RB-PTS showed steady recovery of cerebral blood flow (CBF) in the ischemic border from 1 day after infarction, but without recanalization of the proximal MCA branch. Intravital imaging showed high potency of restoring the blood flow by tPA after single vessel-targeted T+RB-PTS. Further, although intravenous tPA failed to restore CBF or attenuate infarction in RB-PTS, it conferred 25% recovery of CBF and 55% reduction of the infarct size in T+RB-PTS (P < .05) if tPA was administered within 2 hours postphotoactivation. These results suggest that T+RB-PTS produces mixed platelet:fibrin clots closer to the clinical thrombus composition and enhanced the sensitivity to tPA-lytic treatment. As such, the modified photothrombosis may be a useful tool to develop more effective thrombolytic therapies of cerebral ischemia.

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“…P-selectin-dependent leukoadhesion to microvascular endothelium greatly increases, and leukocyte emigration ensues (14). Occlusive events and microinfarcts develop in the brain (32,33), and more obvious damage appears in the liver and kidney (23,34). Even without H/R provocation, severe-phenotype sickle mice exhibit substantial pathology such as infarctions in liver, kidney, spleen, and brain (35).…”

Section: Generation Of Omentioning

confidence: 99%

“…Many aspects of I/R pathophysiology likely participate in these events. Cerebrovascular P-selectin expression triggered by NADPH oxidase impedes cerebral microvascular flow (39,48), and H/R provocation triggers microinfarcts (32,33). The brains of sickle mice and patients reveal abnormal blood-brain barrier hyperpermeability (35), a known feature of cerebral I/R models.…”

Section: Local I/r Injury To the Brainmentioning

confidence: 99%

The multifaceted role of ischemia/reperfusion in sickle cell anemia

Hebbel¹,

Belcher²,

Vercellotti³

2020

Journal of Clinical Investigation

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The sickle mutation in the HBB gene encoding β globin results in formation of sickle hemoglobin (HbS) rather than normal HbA. When homozygous, this causes sickle cell anemia (SCA), a unique disease characterized by hemolytic anemia, recurrent vascular occlusions, a systemic inflammatory state, substantial multiorgan disease, foreshortened lifespan, and much suffering. All this stems from the abnormal behaviors of HbS: deoxygenated HbS assembles reversibly into rigid polymers (1), and oxygenated HbS is modestly unstable (2). While the former dominates the disease, the latter does foster development of pathogenic red blood cell (RBC) membrane abnormalities, as reviewed elsewhere (3, 4). Vaso-occlusions punctuate the clinical course with severe acute painful episodes that are unpredictable in occurrence and variable in frequency. Despite its prominence, sickle vaso-occlusion still presents abundant mysteries that have prompted counterpoised queries (5): "Why don't vaso-occlusions occur all the time?" versus "Why do vaso-occlusions occur at all?" The answer to both questions, we believe, is that SCA is a disease powered by ischemia/reperfusion (I/R) injury pathobiology, a conclusion grounded in data from sickle transgenic mice, SCA patients, and the general I/R literature. In particular, I/R pathophysiology underlies the unique inflammatory context of SCA, a state that is cyclic, systemic, intense, complex, unstable, and perpetual. Thus, we regard I/R as the modern formulation of the "vicious cycle" between erythrostasis and occlusion presciently posited by Ham and Castle in 1942 (Figure 1). In this Review, we briefly describe the concept of I/R injury and then emphasize the I/R features of the sickle context that match classical I/R models and diseases. We then link these features to the vascular wall pathobiology of SCA and thence to specific clinical features. We conclude by commenting on therapeutic implications and opportunities.

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Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment

Cited by 13 publications

References 32 publications

Renal protection by atorvastatin in a murine model of sickle cell nephropathy

Renal protection by atorvastatin in a murine model of sickle cell nephropathy

A murine photothrombotic stroke model with an increased fibrin content and improved responses to tPA-lytic treatment

The multifaceted role of ischemia/reperfusion in sickle cell anemia

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