Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression

Jin, Hong; Gebska, Milena A.; Blokhin, Ilya O.; Wilson, Katina M.; Ketsawatsomkron, Pimonrat; Chauhan, Anil K.; Keen, Henry L.; Lentz, Steven R.

doi:10.1161/atvbaha.115.305378

Cited by 36 publications

(25 citation statements)

References 45 publications

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“…Carotid artery thrombosis was induced by direct chemical injury with ferric chloride (FeCl 3 ) as described previously (71). Mice were anesthetized with sodium pentobarbital (70 to 90 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

Gu¹,

Blokhin²,

Wilson³

et al. 2016

JCI Insight

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Reperfusion injury can exacerbate tissue damage in ischemic stroke, but little is known about the mechanisms linking ROS to stroke severity. Here, we tested the hypothesis that protein methionine oxidation potentiates NF-κB activation and contributes to cerebral ischemia/reperfusion injury. We found that overexpression of methionine sulfoxide reductase A (MsrA), an antioxidant enzyme that reverses protein methionine oxidation, attenuated ROS-augmented NF-κB activation in endothelial cells, in part, by protecting against the oxidation of methionine residues in the regulatory domain of calcium/calmodulin-dependent protein kinase II (CaMKII). In a murine model, MsrA deficiency resulted in increased NF-κB activation and neutrophil infiltration, larger infarct volumes, and more severe neurological impairment after transient cerebral ischemia/reperfusion injury. This phenotype was prevented by inhibition of NF-κB or CaMKII. MsrA-deficient mice also exhibited enhanced leukocyte rolling and upregulation of E-selectin, an endothelial NF-κB–dependent adhesion molecule known to contribute to neurovascular inflammation in ischemic stroke. Finally, bone marrow transplantation experiments demonstrated that the neuroprotective effect was mediated by MsrA expressed in nonhematopoietic cells. These findings suggest that protein methionine oxidation in nonmyeloid cells is a key mechanism of postischemic oxidative injury mediated by NF-κB activation, leading to neutrophil recruitment and neurovascular inflammation in acute ischemic stroke.

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Section: Methodsmentioning

confidence: 99%

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

Gu¹,

Blokhin²,

Wilson³

et al. 2016

JCI Insight

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“…As endothelial peroxisome proliferator-activated receptor gamma receptor activation downregulates P-selectin expression and impairs leukocyte-endothelial interaction, this pathway might be an interesting therapeutic target to protect against thrombosis. 44 On the contrary, endothelial angiopoietin-like-protein-2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression. 45 Psoriasis is an inflammatory skin disease associated with increased cardiovascular mortality.…”

Section: Endothelial Inflammationmentioning

confidence: 99%

Endothelium

Boulanger

2016

ATVB

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“…1 HNMR (500 Hz) and 13 C NMR (125 Hz) spectra were acquired on a Bruker AVANCE Ⅱ 500 in CDCl 3 with TMS as internal standard, or in DMSO-d6 and chemical shifts were expressed with ppm. Melting points were measured in capillary tubes on an electrothermal SM/XMP apparatus and without correction.…”

Section: General Proceduresmentioning

confidence: 99%

IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo

Zhu

Zhao

et al. 2017

J. Mater. Chem. B

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Thrombosis seriously threatens human health worldwide. Tetrahydroisoquinoline-3-carboxylic acid (IQCA) is an antithrombotic agent, while Thr-Ala-Arg-Gly-Asp(Ser)-Ser (TASS) can target thrombus. In the discovery of nano-delivery system for targeting thrombus tetrahydroisoquinoline-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Ser)-Ser (IQCA-TASS) was designed here. In vitro IQCA-TASS acted on P-selectin and down-regulated P-selectin expression. The IC 50 values of IQCA-TASS against the platelet aggregation induced by four aggregators were less than 0.45 nM.In vivo IQCA-TASS targeted thrombus, released IQCA and TASS inside thrombus, showed dose-dependent anti-thrombotic action, of which the minimal effective dose was 1 nmol/kg, and showed anti-inflammatory action. Even the dose been up to 1 μmol/kg, a dose of 1000 times of the minimal effective dose, IQCA-TASS still induced no toxic reaction. In rat plasma IQCA-TASS forms the nanoparticles of less than 41 nm in diameter. The interactions of the nanoparticles with both resting and activated platelets were imaged. In conclusion, IQCA-TASS should be a safe nano-medicine capable of targeting thrombus and releasing the anti-thrombotic/anti-inflammatory pharmacophores in the disease site.

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Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression

Cited by 36 publications

References 45 publications

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

Endothelium

IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo

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