| In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity. | |
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MedLine Citation:
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PMID: 22534729 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo. Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL-ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL-ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL-ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL-ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques. |
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Authors:
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Emilia S Olson; Michael A Whitney; Beth Friedman; Todd A Aguilera; Jessica L Crisp; Fred M Baik; Tao Jiang; Stephen M Baird; Sotirios Tsimikas; Roger Y Tsien; Quyen T Nguyen |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-26 |
Journal Detail:
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Title: Integrative biology : quantitative biosciences from nano to macro Volume: - ISSN: 1757-9708 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101478378 Medline TA: Integr Biol (Camb) Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0647, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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