P364. Understanding the Role of Mitochondrial Dysfunction and Senescence in Age-Related Aortic Disease
Presented During: POD Abstracts (Available for viewing in the exhibit hall for the duration of the meeting)
University of Washington School of Medicine
Seattle, WA
United States - Contact Me
Integrated Cardiothoracic Surgery Resident at the University of Washington. Interested in aortic surgery and aging research.
Thursday, April 25, 2024: 5:38 PM - 7:00 PM
Sheraton Times Square
Room: Central Park
Description
Objective: Aging is a well-known risk factor for aortic dilation, aneurysm formation, and dissection. Genetic aortopathies have also been shown to have an "early-aging" phenotype. Given the role of both mitochondrial dysfunction and senescence in age-related disease, we seek to better characterize the role of these processes in aortic pathology, and investigate the effect of therapeutics targeting these pathways in treating aortic disease.
Methods: Four model systems will be utilized. The first is a model of natural aging, comparing 24-month-old C57BL/6 mice to 3- to 8-month-old C57BL/6 mice. The second model will utilize 24-month-old C57BL/6 mice treated with four weeks of Angiotensin II to induce hypertensive aortic disease. The third model will utilize 4-week-old C57BL/6 mice treated with Beta-Aminoproprionitrile to induce connective tissue-related aortic disease via lysyl oxidase inhibition. The final model will utilize primary aortic smooth muscle cells cultured from patients undergoing cardiac surgery, from both diseased and non-diseased aortas. Each model will be treated with either standard saline/culture media or elamipretide, a mitochondrial targeted therapeutic that has been shown to improve mitochondrial function, senescence, and age-related dysfunction in multiple organ systems. After treatment endpoint, the mice will be euthanized and the aorta will be harvested. Mitochondrial function will be assessed using direct tissue respirometry and mitochondrial content assays. Senescence will be investigated via senescence-associated beta galactosidase staining along with immunoblotting and immunofluorescent assessment of the senescence markers p16/CDKN2a and p53. Histologic assessment of the aorta will be done to determine media thickness and frequency elastin breaks. Primary smooth muscle cells will be assessed for mitochondrial function and senescence as noted above.
Results: Data is currently being collected for this project. Available data reveals a non- statistically significant higher respiratory capacity in young wild type mouse aortas compared to older wild type aortas (p=0.46), and a significantly larger aorta in older wild type mice compared to young wild type mice (p=0.03). However, appropriate power numbers have not yet been reached for definitive analysis.
Conclusions: Based on early data, the aortas of wild type older C57BL/6 mice are on average larger and may have depressed mitochondrial function compared to young wild type C57BL/6 mice. Complete results for the first model (natural aging) will be analyzed and available by April of 2024.
Authors
Arjune Dhanekula (1), Scott DeRoo (2), Chris Burke (2), Billiana Hwang (2), Michael Mulligan (3), Jay Pal (4), David Marcinek (2)
Institutions
(1) University of Washington Medical Center, United States, (2) University of Washington, Seattle, WA, (3) UWMC, Seattle, WA, (4) UCHealth, Aurora, CO
Methods: Four model systems will be utilized. The first is a model of natural aging, comparing 24-month-old C57BL/6 mice to 3- to 8-month-old C57BL/6 mice. The second model will utilize 24-month-old C57BL/6 mice treated with four weeks of Angiotensin II to induce hypertensive aortic disease. The third model will utilize 4-week-old C57BL/6 mice treated with Beta-Aminoproprionitrile to induce connective tissue-related aortic disease via lysyl oxidase inhibition. The final model will utilize primary aortic smooth muscle cells cultured from patients undergoing cardiac surgery, from both diseased and non-diseased aortas. Each model will be treated with either standard saline/culture media or elamipretide, a mitochondrial targeted therapeutic that has been shown to improve mitochondrial function, senescence, and age-related dysfunction in multiple organ systems. After treatment endpoint, the mice will be euthanized and the aorta will be harvested. Mitochondrial function will be assessed using direct tissue respirometry and mitochondrial content assays. Senescence will be investigated via senescence-associated beta galactosidase staining along with immunoblotting and immunofluorescent assessment of the senescence markers p16/CDKN2a and p53. Histologic assessment of the aorta will be done to determine media thickness and frequency elastin breaks. Primary smooth muscle cells will be assessed for mitochondrial function and senescence as noted above.
Results: Data is currently being collected for this project. Available data reveals a non- statistically significant higher respiratory capacity in young wild type mouse aortas compared to older wild type aortas (p=0.46), and a significantly larger aorta in older wild type mice compared to young wild type mice (p=0.03). However, appropriate power numbers have not yet been reached for definitive analysis.
Conclusions: Based on early data, the aortas of wild type older C57BL/6 mice are on average larger and may have depressed mitochondrial function compared to young wild type C57BL/6 mice. Complete results for the first model (natural aging) will be analyzed and available by April of 2024.
Authors
Arjune Dhanekula (1), Scott DeRoo (2), Chris Burke (2), Billiana Hwang (2), Michael Mulligan (3), Jay Pal (4), David Marcinek (2)
Institutions
(1) University of Washington Medical Center, United States, (2) University of Washington, Seattle, WA, (3) UWMC, Seattle, WA, (4) UCHealth, Aurora, CO
Presentation Duration
PODS will be on display in the exhibit hall for the duration of the meeting during exhibit hall hours. PODS will also be available for viewing on the meeting website. There is no formal presentation associated with your POD, but we encourage you to visit the PODS area during breaks to connect with those viewing.