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Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces

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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.
Keywords
aging, aortic stiffness, cytoskeletal dynamics, Genome Wide Association Study, vascular smooth muscle, PULSE-WAVE VELOCITY, MUSCLE-CELL STIFFNESS, ARTERIAL STIFFNESS, FOCAL ADHESION, INDEPENDENT PREDICTOR, ACTIN POLYMERIZATION, VINCULIN BINDING, BLOOD-PRESSURE, SMOOTH, IDENTIFICATION

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MLA
Nicholson, Christopher J., et al. “Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.” JOURNAL OF THE AMERICAN HEART ASSOCIATION, vol. 7, no. 15, 2018, doi:10.1161/JAHA.118.008926.
APA
Nicholson, C. J., Singh, K., Saphirstein, R. J., Gao, Y. Z., Li, Q., Chiu, J. G., … De Backer, G. (2018). Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 7(15). https://doi.org/10.1161/JAHA.118.008926
Chicago author-date
Nicholson, Christopher J, Kuldeep Singh, Robert J Saphirstein, Yuan Z Gao, Qian Li, Joanna G Chiu, Paul Leavis, et al. 2018. “Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.” JOURNAL OF THE AMERICAN HEART ASSOCIATION 7 (15). https://doi.org/10.1161/JAHA.118.008926.
Chicago author-date (all authors)
Nicholson, Christopher J, Kuldeep Singh, Robert J Saphirstein, Yuan Z Gao, Qian Li, Joanna G Chiu, Paul Leavis, Germaine C Verwoert, GF Mitchell, Tyrone Porter, Kathleen G Morgan, the AortaGen Consortium, Ernst Rietzschel, Marc De Buyzere, Patrick Segers, Sofie Bekaert, Dirk De Bacquer, Tim De Meyer, Thierry Gillebert, Lucas Van Bortel, and Gui De Backer. 2018. “Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.” JOURNAL OF THE AMERICAN HEART ASSOCIATION 7 (15). doi:10.1161/JAHA.118.008926.
Vancouver
1.
Nicholson CJ, Singh K, Saphirstein RJ, Gao YZ, Li Q, Chiu JG, et al. Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces. JOURNAL OF THE AMERICAN HEART ASSOCIATION. 2018;7(15).
IEEE
[1]
C. J. Nicholson et al., “Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces,” JOURNAL OF THE AMERICAN HEART ASSOCIATION, vol. 7, no. 15, 2018.
@article{8622949,
  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.}},
  articleno    = {{e008926}},
  author       = {{Nicholson, Christopher J and Singh, Kuldeep and Saphirstein, Robert J and Gao, Yuan Z and Li, Qian and Chiu, Joanna G and Leavis, Paul and Verwoert, Germaine C and Mitchell, GF and Porter, Tyrone and Morgan, Kathleen G and AortaGen Consortium, the and Rietzschel, Ernst and De Buyzere, Marc and Segers, Patrick and Bekaert, Sofie and De Bacquer, Dirk and De Meyer, Tim and Gillebert, Thierry and Van Bortel, Lucas and De Backer, Gui}},
  issn         = {{2047-9980}},
  journal      = {{JOURNAL OF THE AMERICAN HEART ASSOCIATION}},
  keywords     = {{aging,aortic stiffness,cytoskeletal dynamics,Genome Wide Association Study,vascular smooth muscle,PULSE-WAVE VELOCITY,MUSCLE-CELL STIFFNESS,ARTERIAL STIFFNESS,FOCAL ADHESION,INDEPENDENT PREDICTOR,ACTIN POLYMERIZATION,VINCULIN BINDING,BLOOD-PRESSURE,SMOOTH,IDENTIFICATION}},
  language     = {{eng}},
  number       = {{15}},
  pages        = {{17}},
  title        = {{Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces}},
  url          = {{http://doi.org/10.1161/JAHA.118.008926}},
  volume       = {{7}},
  year         = {{2018}},
}

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