Abstract
Individuals with a bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation and dissection. Loss of aortic medial smooth muscle cells (SMCs) and disruption of the extracellular matrix are well-recognized pathologies, but the underlying cellular mechanisms remain elusive. We tested the hypothesis that the dilated aorta in patients with BAV was marked by accelerated cellular aging. Samples of human ascending aorta were obtained from individuals with BAV undergoing thoracic aorta replacement (n=37, age 54.7±2.2, aortic diameter 4.8±0.9 cm) or patients with a tricuspid aortic valve and non-dilated aorta undergoing heart transplantation or coronary bypass procedures (n=6, age 55.3±8.1, aortic diameter 3.1±0.3 cm). Assessment of fresh aortic samples for senescence-associated β-galactosidase revealed evidence for rare medial cell senescence that was 4.2-fold more prevalent in dilated aortas (0.83±0.10%) than in non-dilated aortas (0.20±0.10%, p=0.048). Expression of p16 was abundantly detected in medial SMCs within dilated aortas (27.0±2.1%) and 3-fold more abundant than in non-dilated aortas (8.9±1.8%, p<0.0001). Interestingly, immunostaining for γH2A.X (phosphorylated Ser139) revealed discrete nuclear DNA double-strand breakage signals in 25.7±3.8% of medial cells in dilated aortas from patients with BAV, which was 2.3-fold higher than that found in non-dilated aortas (11.0±4.9, p=0.03). CONCLUSION: These findings identify a previously unrecognized phenomenon of accelerated SMC aging in the aortas of patients with BAV, with cellular senescence and unresolved DNA breaks. Accelerated cell aging could thus be a driver of aortic wall degeneration in these patients and a potential therapeutic target.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Arteriosclerosis, Thrombosis, and Vascular Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
