02623nas a2200265 4500008004100000022001400041245011400055210006900169260001600238490000600254520180700260100003002067700001902097700002702116700001702143700001302160700002002173700001702193700002602210700001802236700001902254700002402273710002402297856003602321 2018 eng d a2047-998000aReversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.0 aReversal of AgingInduced Increases in Aortic Stiffness by Target c2018 Jul 180 v73 a

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 () locus is associated with carotid-femoral pulse wave velocity (rs600420, =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.

1 aNicholson, Christopher, J1 aSingh, Kuldeep1 aSaphirstein, Robert, J1 aGao, Yuan, Z1 aLi, Qian1 aChiu, Joanna, G1 aLeavis, Paul1 aVerwoert, Germaine, C1 aMitchell, G F1 aPorter, Tyrone1 aMorgan, Kathleen, G1 aAortaGen Consortium uhttps://chs-nhlbi.org/node/7807