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dc.contributor.authorNicholson, Christopheren_US
dc.contributor.authorSingh, Kuldeepen_US
dc.contributor.authorSaphirstein, Roberten_US
dc.contributor.authorGao, Yuanen_US
dc.contributor.authorLi, Qianen_US
dc.contributor.authorChiu, Joannaen_US
dc.contributor.authorLeavis, Paulen_US
dc.contributor.authorVerwoert, Germaineen_US
dc.contributor.authorMitchell, G. F.en_US
dc.contributor.authorPorter, Tyroneen_US
dc.contributor.authorMorgan, Kathleenen_US
dc.date.accessioned2020-01-06T19:28:53Z
dc.date.available2020-01-06T19:28:53Z
dc.date.issued2018-07-06
dc.identifier.citationChristopher Nicholson, Kuldeep Singh, Robert Saphirstein, Yuan Gao, Qian Li, Joanna Chiu, Paul Leavis, Germaine Verwoert, GF Mitchell, Tyrone Porter, Kathleen Morgan. 2018. "Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces." Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease, Volume 7, Issue 15,
dc.identifier.issn2047-9980
dc.identifier.urihttps://hdl.handle.net/2144/39043
dc.description.abstractBACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome‐wide association study of carotid‐femoral pulse wave velocity. Common genetic variation in the N‐WASP (WASL) locus is associated with carotid‐femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N‐WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N‐WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin‐vinculin interfaces similarly decreased aging‐induced ex vivo active stiffness by on‐target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound‐targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein‐protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein‐protein interfaces may lead to substantive dynamic modulation of aortic stiffness.en_US
dc.language.isoen_US
dc.publisherWileyen_US
dc.relation.ispartofJournal of the American Heart Association : Cardiovascular and Cerebrovascular Disease
dc.rightsAttribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectGenome wide association studyen_US
dc.subjectAgingen_US
dc.subjectAortic stiffnessen_US
dc.subjectCytoskeletal dynamicsen_US
dc.subjectVascular smooth muscleen_US
dc.titleReversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfacesen_US
dc.typeArticleen_US
dc.description.versionPublished versionen_US
dc.identifier.doiDOI: 10.1161/JAHA.118.008926
pubs.elements-sourcemanual-entryen_US
pubs.notesEmbargo: Not knownen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Engineeringen_US
pubs.organisational-groupBoston University, College of Engineering, Department of Mechanical Engineeringen_US
pubs.publication-statusPublisheden_US
dc.identifier.mycv453991


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International