Abstract | OBJECTIVE: A role for thrombin in the pathogenesis of atherosclerosis has been suggested through clinical and experimental studies revealing a critical link between the coagulation system and inflammation. Although approved drugs for inhibition of thrombin and thrombin-related signaling have demonstrated efficacy, their clinical application to this end may be limited because of significant potential for bleeding side effects. Thus, we sought to implement a plaque-localizing nanoparticle-based approach to interdict thrombin-induced inflammation and hypercoagulability in atherosclerosis. APPROACH AND RESULTS: We deployed a novel magnetic resonance spectroscopic method to quantify the severity of endothelial damage for correlation with traditional metrics of vessel procoagulant activity after dye-laser injury in fat-fed apolipoprotein E-null mice. We demonstrate that a 1-month course of treatment with antithrombin nanoparticles carrying the potent thrombin inhibitor PPACK (d-phenylalanyl-l-prolyl-l-arginyl chloromethylketone) nanoparticle (1) reduces the expression and secretion of proinflammatory and procoagulant molecules, (2) diminishes plaque procoagulant activity without the need for systemic anticoagulation, (3) rapidly restores disrupted vascular endothelial barriers, and (4) retards plaque progression in lesion-prone areas. CONCLUSIONS:
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Authors | Rohun U Palekar, Andrew P Jallouk, Jacob W Myerson, Hua Pan, Samuel A Wickline |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 36
Issue 3
Pg. 446-55
(Mar 2016)
ISSN: 1524-4636 [Electronic] United States |
PMID | 26769047
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2016 American Heart Association, Inc. |
Chemical References |
- Amino Acid Chloromethyl Ketones
- Antithrombins
- Apolipoproteins E
- Inflammation Mediators
- Thrombin
- phenylalanyl-prolyl-arginine-chloromethyl ketone
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Topics |
- Amino Acid Chloromethyl Ketones
(pharmacokinetics, pharmacology)
- Animals
- Antithrombins
(pharmacokinetics, pharmacology)
- Apolipoproteins E
(deficiency, genetics)
- Atherosclerosis
(drug therapy, genetics, metabolism, pathology)
- Blood Coagulation
(drug effects)
- Capillary Permeability
(drug effects)
- Carotid Artery Injuries
(drug therapy, metabolism, pathology)
- Cells, Cultured
- Diet, High-Fat
- Disease Models, Animal
- Endothelial Cells
(drug effects, metabolism, pathology)
- Endothelium, Vascular
(drug effects, metabolism, pathology)
- Humans
- Inflammation Mediators
(metabolism)
- Magnetic Resonance Spectroscopy
- Male
- Mice, Knockout
- Nanoparticles
- Plaque, Atherosclerotic
- Signal Transduction
(drug effects)
- Thrombin
(antagonists & inhibitors, metabolism)
- Thrombosis
(genetics, metabolism, pathology, prevention & control)
- Time Factors
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