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

Autor: Nicholson, Christopher J, Singh, Kuldeep, Saphirstein, Robert J, Gao, Yuan Z, Li, Qian, Chiu, Joanna G, Leavis, Paul, Verwoert, Germaine C, Mitchell, GF, Porter, Tyrone, Morgan, Kathleen G, AortaGen Consortium, the, Rietzschel, Ernst, De Buyzere, Marc, Segers, Patrick, Bekaert, Sofie, De Bacquer, Dirk, De Meyer, Tim, Gillebert, Thierry, Van Bortel, Lucas, De Backer, Gui
Přispěvatelé: Epidemiology
Rok vydání: 2018
Předmět:
0301 basic medicine
Aging
Smooth Muscle Proliferation and Differentiation
VINCULIN BINDING
Vascular smooth muscle
Aorta
Thoracic
Blood Pressure
BLOOD-PRESSURE
030204 cardiovascular system & hematology
Vascular Medicine
Genome Wide Association Study
Muscle
Smooth
Vascular
Mice
0302 clinical medicine
Medicine and Health Sciences
Medicine
Cytoskeleton
Cells
Cultured
Original Research
Vinculin binding
MUSCLE-CELL STIFFNESS
FOCAL ADHESION
SMOOTH
Hypertension
cardiovascular system
Aortic stiffness
Cell Biology/Structural Biology
ARTERIAL STIFFNESS
Cardiology and Cardiovascular Medicine
aortic stiffness
macromolecular substances
Pulse Wave Analysis
Polymorphism
Single Nucleotide
cytoskeletal dynamics
Focal adhesion
03 medical and health sciences
Vascular Stiffness
Vascular Biology
medicine.artery
INDEPENDENT PREDICTOR
Animals
Humans
ACTIN POLYMERIZATION
Aorta
IDENTIFICATION
business.industry
aging
Biology and Life Sciences
DNA
medicine.disease
Mice
Inbred C57BL
Cytoskeletal Proteins
030104 developmental biology
Blood pressure
vascular smooth muscle
PULSE-WAVE VELOCITY
Biophysics
Arterial stiffness
Contractile function
business
Cell Signalling/Signal Transduction
Genome-Wide Association Study
Zdroj: JOURNAL OF THE AMERICAN HEART ASSOCIATION
Journal of the American Heart Association, 7(15):e008926. Wiley
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 0039-2499
2047-9980
Popis: 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.
Databáze: OpenAIRE
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