Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth
Identifieur interne : 006022 ( Main/Exploration ); précédent : 006021; suivant : 006023Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth
Auteurs : Won Gil Cho ; Romulo J. C. Albuquerque [États-Unis] ; Mark E. Kleinman ; Valeria Tarallo [Italie] ; Adelaide Greco [Italie] ; Miho Nozaki ; Martha G. Green ; Judit Z. Baffi ; Balamurali K. Ambati [États-Unis] ; Massimo De Falco [Italie] ; Jonathan S. Alexander [États-Unis] ; Arturo Brunetti [Italie] ; Sandro De Falco [Italie] ; Jayakrishna Ambati [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2009.
Abstract
Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. We reported recently that 21-nt or longer small interfering RNAs (siRNAs) can suppress hemangiogenesis in mouse models of choroidal neovascularization and dermal wound healing independently of RNA interference by directly activating Toll-like receptor 3 (TLR3), a double-stranded RNA immune receptor, on the cell surface of blood endothelial cells. Here, we show that a 21-nt nontargeted siRNA suppresses both hemangiogenesis and lymphangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt siRNA targeting vascular endothelial growth factor-A. In contrast, a 7-nt nontargeted siRNA, which is too short to activate TLR3, does not block hemangiogenesis or lymphangiogenesis in these models. Exposure to 21-nt siRNA, which we demonstrate is not internalized unless cell-permeating moieties are used, triggers phosphorylation of cell surface TLR3 on lymphatic endothelial cells and induces apoptosis. These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.
Url:
DOI: 10.1073/pnas.0812317106
PubMed: 19359485
PubMed Central: 2678451
Affiliations:
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C." last="Albuquerque">Romulo J. C. Albuquerque</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2">Physiology, University of Kentucky, Lexington, KY 40536;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Physiology, University of Kentucky, Lexington</wicri:cityArea></affiliation></author><author><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. Kleinman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Tarallo, Valeria" sort="Tarallo, Valeria" uniqKey="Tarallo V" first="Valeria" last="Tarallo">Valeria Tarallo</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy;</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples 80131</wicri:regionArea><wicri:noRegion>Naples 80131</wicri:noRegion></affiliation></author><author><name sortKey="Greco, Adelaide" sort="Greco, Adelaide" uniqKey="Greco A" first="Adelaide" last="Greco">Adelaide Greco</name><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Biomorphological and Functional Sciences, University Federico II, Istituto di Biostrutture e Bioimmagini-Consiglio Nazionale delle Ricerche and Centro di Ingegneria Genetica, Naples 80131, Italy;</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biomorphological and Functional Sciences, University Federico II, Istituto di Biostrutture e Bioimmagini-Consiglio Nazionale delle Ricerche and Centro di Ingegneria Genetica, Naples 80131</wicri:regionArea><wicri:noRegion>Naples 80131</wicri:noRegion></affiliation></author><author><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Green, Martha G" sort="Green, Martha G" uniqKey="Green M" first="Martha G." last="Green">Martha G. Green</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><affiliation wicri:level="2"><nlm:aff id="aff5">Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Utah</region></placeName><wicri:cityArea>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff6">Department of Ophthalmology, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT 84148;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Utah</region></placeName><wicri:cityArea>Department of Ophthalmology, Veterans Affairs Salt Lake City Health Care System, Salt Lake City</wicri:cityArea></affiliation></author><author><name sortKey="De Falco, Massimo" sort="De Falco, Massimo" uniqKey="De Falco M" first="Massimo" last="De Falco">Massimo De Falco</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff7">Department of Anesthesiological, Surgical and Emergency Sciences, V Unit of Surgery and Advanced Surgical Procedures, Second University of Naples, Naples 80100, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Anesthesiological, Surgical and Emergency Sciences, V Unit of Surgery and Advanced Surgical Procedures, Second University of Naples, Naples 80100</wicri:regionArea><wicri:noRegion>Naples 80100</wicri:noRegion></affiliation></author><author><name sortKey="Alexander, Jonathan S" sort="Alexander, Jonathan S" uniqKey="Alexander J" first="Jonathan S." last="Alexander">Jonathan S. Alexander</name><affiliation wicri:level="2"><nlm:aff id="aff8">Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Louisiane</region></placeName><wicri:cityArea>Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport</wicri:cityArea></affiliation></author><author><name sortKey="Brunetti, Arturo" sort="Brunetti, Arturo" uniqKey="Brunetti A" first="Arturo" last="Brunetti">Arturo Brunetti</name><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Biomorphological and Functional Sciences, University Federico II, Istituto di Biostrutture e Bioimmagini-Consiglio Nazionale delle Ricerche and Centro di Ingegneria Genetica, Naples 80131, Italy;</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biomorphological and Functional Sciences, University Federico II, Istituto di Biostrutture e Bioimmagini-Consiglio Nazionale delle Ricerche and Centro di Ingegneria Genetica, Naples 80131</wicri:regionArea><wicri:noRegion>Naples 80131</wicri:noRegion></affiliation></author><author><name sortKey="De Falco, Sandro" sort="De Falco, Sandro" uniqKey="De Falco S" first="Sandro" last="De Falco">Sandro De Falco</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy;</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples 80131</wicri:regionArea><wicri:noRegion>Naples 80131</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2">Physiology, University of Kentucky, Lexington, KY 40536;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Physiology, University of Kentucky, Lexington</wicri:cityArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. We reported recently that 21-nt or longer small interfering RNAs (siRNAs) can suppress hemangiogenesis in mouse models of choroidal neovascularization and dermal wound healing independently of RNA interference by directly activating Toll-like receptor 3 (TLR3), a double-stranded RNA immune receptor, on the cell surface of blood endothelial cells. Here, we show that a 21-nt nontargeted siRNA suppresses both hemangiogenesis and lymphangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt siRNA targeting vascular endothelial growth factor-A. In contrast, a 7-nt nontargeted siRNA, which is too short to activate TLR3, does not block hemangiogenesis or lymphangiogenesis in these models. Exposure to 21-nt siRNA, which we demonstrate is not internalized unless cell-permeating moieties are used, triggers phosphorylation of cell surface TLR3 on lymphatic endothelial cells and induces apoptosis. These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.</p></div></front></TEI><affiliations><list><country><li>Italie</li><li>États-Unis</li></country><region><li>Kentucky</li><li>Louisiane</li><li>Utah</li></region></list><tree><noCountry><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><name sortKey="Cho, Won Gil" sort="Cho, Won Gil" uniqKey="Cho W" first="Won Gil" last="Cho">Won Gil Cho</name><name sortKey="Green, Martha G" sort="Green, Martha G" uniqKey="Green M" first="Martha G." last="Green">Martha G. Green</name><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. Kleinman</name><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name></noCountry><country name="États-Unis"><region name="Kentucky"><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name></region><name sortKey="Alexander, Jonathan S" sort="Alexander, Jonathan S" uniqKey="Alexander J" first="Jonathan S." last="Alexander">Jonathan S. Alexander</name><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name></country><country name="Italie"><noRegion><name sortKey="Tarallo, Valeria" sort="Tarallo, Valeria" uniqKey="Tarallo V" first="Valeria" last="Tarallo">Valeria Tarallo</name></noRegion><name sortKey="Brunetti, Arturo" sort="Brunetti, Arturo" uniqKey="Brunetti A" first="Arturo" last="Brunetti">Arturo Brunetti</name><name sortKey="De Falco, Massimo" sort="De Falco, Massimo" uniqKey="De Falco M" first="Massimo" last="De Falco">Massimo De Falco</name><name sortKey="De Falco, Sandro" sort="De Falco, Sandro" uniqKey="De Falco S" first="Sandro" last="De Falco">Sandro De Falco</name><name sortKey="Greco, Adelaide" sort="Greco, Adelaide" uniqKey="Greco A" first="Adelaide" last="Greco">Adelaide Greco</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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