Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces. Issue 15 (7th August 2018)

• Record Type: Journal Article
• Authors: Nicholson, Christopher J.; Singh, Kuldeep; Saphirstein, Robert J.; Gao, Yuan Z.; Li, Qian; Chiu, Joanna G.; Leavis, Paul; Verwoert, Germaine C.; Mitchell, G. F.; Porter, Tyrone; Morgan, Kathleen G.
• Other Names: Tarasov Kirill V. investigator.; Isaacs Aaron investigator.; Smith Albert V. investigator.; Yasmin investigator.; Rietzschel Ernst R. investigator.; Tanaka Toshiko investigator.; Liu Yongmei investigator.; Parsa Afshin investigator.; Najjar Samer S. investigator.; O'Shaughnessy Kevin M. investigator.; Sigurdsson Sigurdur investigator.; De Buyzere Marc L. investigator.; Larson Martin G. investigator.; Sie Mark P. S. investigator.; Andrews Jeanette S. investigator.; Post Wendy S. investigator.; Mattace‐Raso Francesco U. S. investigator.; McEniery Carmel M. investigator.; Eiriksdottir Gudny investigator.; Segers Patrick investigator.; Vasan Ramachandran S. investigator.; van Rijn Marie Josee E. investigator.; Howard Timothy D. investigator.; McArdle Patrick F. investigator.; Dehghan Abbas investigator.; Jewell Elizabeth investigator.; Newhouse Stephen J. investigator.; Bekaert Sofie investigator.; Hamburg Naomi M. investigator.; Newman Anne B. investigator.; Hofman Albert investigator.; Scuteri Angelo investigator.; De Bacquer Dirk investigator.; Ikram Mohammad Arfan investigator.; Psaty Bruce investigator.; Fuchsberger Christian investigator.; Olden Matthias investigator.; Wain Louise V. investigator.; Elliott Paul investigator.; Smith Nicholas L. investigator.; Felix Janine F. investigator.; Erdmann Jeanette investigator.; Vita Joseph A. investigator.; Sutton‐Tyrrell Kim investigator.; Sijbrands Eric J. G. investigator.; Sanna Serena investigator.; Launer Lenore J. investigator.; De Meyer Tim investigator.; Johnson Andrew D. investigator.; Schut Anna F. C. investigator.; Herrington David M. investigator.; Rivadeneira Fernando investigator.; Uda Manuela investigator.; Wilkinson Ian B. investigator.; Aspelund Thor investigator.; Gillebert Thierry C. investigator.; Van Bortel Luc investigator.; Benjamin Emelia J. investigator.; Oostra Ben A. investigator.; Ding Jingzhong investigator.; Gibson Quince investigator.; Uitterlinden André G. investigator.; Abecasis Gonçalo R. investigator.; Cockcroft John R. investigator.; Gudnason Vilmundur investigator.; De Backer Guy G. investigator.; Ferrucci Luigi investigator.; Harris Tamara B. investigator.; Shuldiner Alan R. investigator.; van Duijn Cornelia M. investigator.; Levy Daniel investigator.; Lakatta Edward G. investigator.; Witteman Jacqueline C. M. investigator.;
• Is Part Of: Journal of the American Heart Association. Volume 7:Issue 15(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-08-07
• Subjects: aging -- aortic stiffness -- cytoskeletal dynamics -- Genome Wide Association Study -- vascular smooth muscle; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.118.008926
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : Background: 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.