Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is an independent risk factor for CVD. With the expansion of the aging population, by 2030 >40% of the population is projected to have CVD. Advanced age is accompanied by blunted endothelium-dependent dilation (EDD), reductions in nitric oxide (NO) bioavailability and increased large artery stiffness, important contributors to CVD risk. Arterial inflammation plays an important role in these processes but the precise link is unclear. We will utilize a translational approach to determine whether T cells play a role in age-related chronic arterial inflammation and subsequent dysfunction. First, we hypothesize that with aging, pro-inflammatory T cells accumulate around arteries and exacerbate age-related arterial dysfunction. To test this, we will assess arterial function, immune cell infiltration and inflammatory subtypes in young and old mice with T cells intact, depleted or inhibited. In addition, we will employ adoptive transfer to determine whether age-related arterial dysfunction results from intrinsic age-related changes to T cells, increased T cell recruitment to the aged artery, or both. Second, we hypothesize that T cells from older human donors will home to the vasculature of humanized immuno-deficient mice and induce inflammation and subsequent arterial dysfunction. To test this hypothesis, we will adoptively transfer T cells from young and older healthy human donors to young and old NOD-scid/?cnull/A2 humanized mice and assess immune cell infiltration, inflammation, arterial function, and ROS. Third, we hypothesize that inhibition of T cell activation will improve arterial function in older adults. To test this hypothesis, we will assess vascular function and endothelial cell and T cell inflammatory phenotype in older humans before and after treatment with placebo or a T cell inhibitor, Abatacept. The results of these studies will provide insight into the etiology of age-related arterial dysfunction and identify previously unexplored targets for diagnostics and intervention with the significant goal of maintaining cardiovascular health in the elderly.

Public Health Relevance

Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a primary risk factor for CVD primarily due to dysfunction of the arteries. Arterial inflammation appears to play a role in this dysfunction but the precise link is not clear. The results of the proposed studies will indicate whether T cells from the immune system directly mediate age-related vascular dysfunction and have potential to identify specific targets that may be used for early detection and/or drug treatment to reduce CVD burden in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG060395-01A1
Application #
9748129
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Kerr, Candace L
Project Start
2019-04-15
Project End
2024-01-31
Budget Start
2019-04-15
Budget End
2020-01-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112