Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces

• Published in: Journal of the American Heart Association 2018-07, Vol.7 (15)
• Main 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
• Format: Article
• Language: English
• Subjects: Aging; Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Aorta, Thoracic - physiopathology; aortic stiffness; Blood Pressure; Cells, Cultured; cytoskeletal dynamics; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; DNA - genetics; Genome Wide Association Study; Genome-Wide Association Study - methods; Humans; Hypertension - genetics; Hypertension - pathology; Hypertension - physiopathology; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Original Research; Polymorphism, Single Nucleotide; Pulse Wave Analysis; vascular smooth muscle; Vascular Stiffness - physiology
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.118.008926

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. 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. 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.