Adverse childhood experiences (ACEs) are directly related to cardiovascular morbidity and
mortality, and impaired vascular endothelial function (VEF) is an independent predictor
of future cardiovascular disease (CVD) risk [1, 2]. Previous work from our lab (IRB
202010095) and others [3] demonstrates impaired VEF in young adults with prior exposure
to ACEs even in the absence of clinical CVD risk factors. Sirtuin 1 (SIRT1) is a class
III histone deacetylase (HDAC) that plays a role in regulating vascular homeostasis and
reductions in SIRT1 are associated with age-related endothelial dysfunction [4]. We have
shown that ACEs-related impairments in VEF are accompanied by reductions in SIRT1 [5].
However, the mechanisms by which ACE exposure promotes VEF remain unknown. The goal of
this project is to establish proof of concept that alterations in vascular SIRT1
expression and activity mediate premature vascular aging in individuals with >=4 ACEs
compared to those with 0 ACEs and that, because NAD+ is an essential substrate for SIRT1,
increasing NAD+ bioavailability will restore VEF in those with >=4 ACEs.
Thus, we will use a robust translational approach coupling in vivo and in vitro measures
of endothelial function, inflammation, oxidative stress, and SIRT1 expression and
activity in young adults with (n=30-35) versus without (n=30-35) ACE exposure in a
cross-sectional study, and during a randomized controlled trial employing a novel 4-week
nicotinamide riboside (NR) supplementation approach to increase SIRT1 activity by
increasing cellular NAD+ in ACE+ (n=15/group) to accomplish the following specific aims:
Determine the mechanisms by which ACE exposure alters the regulation of VEF by
SIRT1. We hypothesize that compared to those without ACEs (ACE-), ACE+ will have
(H1a) elevated endothelial oxidative stress and inflammation, (H1b) accompanied by
reduced endothelial SIRT1 expression and increased p66SHC expression and acetylation
of p65 and p53, (H1c) in association with lower VEF.
Determine how targeting SIRT1 by increasing NAD+ bioavailability affects VEF in
young adults with ACEs. We hypothesize that systemic NR supplementation will (H2a)
augment cellular SIRT1 activity and (H2b) improve VEF in ACE+.
[1] Felitti, V.J., Anda, R.F., Nordenberg, D., Williamson, D.F., Spitz, A.M., Edwards,
V., Koss, M.P., & Marks, J.S. (1998). Relationship of childhood abuse and household
dysfunction to many of the leading causes of death in adults: The adverse childhood
experiences (ace) study. American Journal of Preventive Medicine, 14(4), 245-258.
https://doi.org/10.1016/S0749-3797(98)00017-8. [2] Jenkins, N.D.M., & Robinson, A.T.
(2022). How do adverse childhood experiences get under the skin to promote cardiovascular
disease? A focus on vascular health. Function (Oxf), 3(4), zqac032. PMC9279110.
10.1093/function/zqac032. [3] Rodriguez-Miguelez, P., Looney, J., Blackburn, M., Thomas,
J., Pollock, J.S., & Harris, R.A. (2022). The link between childhood adversity and
cardiovascular disease risk: Role of cerebral and systemic vasculature. Function.
10.1093/function/zqac029. [4] Thompson, A. M., Wagner, R., & Rzucidlo, E. M. (2014).
Age-related loss of SirT1 expression results in dysregulated human vascular smooth muscle
cell function. American Journal of Physiology-Heart and Circulatory Physiology, 307(4),
H533-H541. [5] Jenkins, N.D.M., Rogers, E.M., Banks, N.F., Tomko, P.M., Sciarrillo, C.M.,
Emerson, S.R., Taylor, A., & Teague, T.K. (2021). Childhood psychosocial stress is linked
with impaired vascular endothelial function, lower sirt1, and oxidative stress in young
adulthood. Am J Physiol Heart Circ Physiol, 321(3), H532-H541. PMC8461842.
10.1152/ajpheart.00123.2021