Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces
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. ,   AortaGen Consortium, Porter Tyrone , Morgan Kathleen G. , Tarasov Kirill V. , Isaacs Aaron , Smith Albert V. , Yasmin  , Rietzschel Ernst R. , Tanaka Toshiko , Liu Yongmei , Parsa Afshin , Najjar Samer S. , O'Shaughnessy Kevin M. , Sigurdsson Sigurdur , De Buyzere Marc L. , Larson Martin G. , Sie Mark P. S. , Andrews Jeanette S. , Post Wendy S. , Mattace‐Raso Francesco U. S. , McEniery Carmel M. , Eiriksdottir Gudny , Segers Patrick , Vasan Ramachandran S. , van Rijn Marie Josee E. , Howard Timothy D. , McArdle Patrick F. , Dehghan Abbas , Jewell Elizabeth , Newhouse Stephen J. , Bekaert Sofie , Hamburg Naomi M. , Newman Anne B. , Hofman Albert , Scuteri Angelo , De Bacquer Dirk , Ikram Mohammad Arfan , Psaty Bruce , Fuchsberger Christian , Olden Matthias , Wain Louise V. , Elliott Paul , Smith Nicholas L. , Felix Janine F. , Erdmann Jeanette , Vita Joseph A. , Sutton‐Tyrrell Kim , Sijbrands Eric J. G. , Sanna Serena , Launer Lenore J. , De Meyer Tim , Johnson Andrew D. , Schut Anna F. C. , Herrington David M. , Rivadeneira Fernando , Uda Manuela , Wilkinson Ian B. , Aspelund Thor , Gillebert Thierry C. , Van Bortel Luc , Benjamin Emelia J. , Oostra Ben A. , Ding Jingzhong , Gibson Quince , Uitterlinden André G. , Abecasis Gonçalo R. , Cockcroft John R. , Gudnason Vilmundur , De Backer Guy G. , Ferrucci Luigi , Harris Tamara B. , Shuldiner Alan R. , van Duijn Cornelia M. , Levy Daniel , Lakatta Edward G. , Witteman Jacqueline C. M. 
Published: July 2018

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.