Childhood Sirt1 Is a Predictor of Microvascular Function in Adulthood

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INTRODUCTIONSirtuin 1 (Sirt1), an NAD+‐dependent deacetylase, has recently emerged as an anti‐aging protein that is able to protect endothelial cells from insult, including oxidative stress. Lower concentrations of Sirt1 are associated with endothelial dysfunction and subsequent premature vascular aging in both humans and animal models. Microvascular function (MVF), assessed using the cutaneous microcirculation, represents a non‐invasive assessment of vascular aging. Whether or not lower Sirt1 during childhood predisposes adults to a reduced MVF has yet to be investigated.PURPOSEThis study sought to test the hypothesis that lower concentrations of Sirt1 during childhood are associated with a reduced microvascular function during adulthood.METHODSThirty‐seven adults (34 ± 3 yrs) from the Georgia Heart and Stress cohort, a longitudinal study evaluating cardiovascular health, participated in the present study. Sirt1 was assessed in previously collected childhood (17 ± 3 yrs) plasma samples and data were separated into two groups based on the concentrations of Sirt1: <3 mg/dl (LowCS; n=18) and ≥3 mg/dl (HighCS; n=19). MVF was evaluated in all the adults using Laser Doppler flowmetry coupled with two endothelial‐dependent vasodilation protocols: 1) post‐occlusive reactive hyperemia (PORH) and 2) iontophoresis of acetylcholine (ACh). Maximal (max) dilatory capacity was evaluated through local thermal hyperemia (LTH). MVF assessments were evaluated as cutaneous flux and expressed as cutaneous vascular conductance (CVC; cutaneous flux / mean arterial blood pressure).RESULTSNo differences (p=0.488) in resting CVC were observed between groups. However, the LowCS group exhibited a significantly blunted dilation response to both PORH (ΔCVC=−8.9 ± 4.2% CVCmax; p=0.043) and ACh (ΔCVC=−14.6 ± 4.1% CVCmax; p=0.033) when compared with the HighCS group. LTH response tended to be higher in the HighCS when compared to the LowCS (ΔCVC=+0.3 ± 0.3 PU/mm Hg; p=0.321). A strong positive relationship was identified between childhood and adulthood concentrations of Sirt1 (r=0.746; p<0.0001). In addition, positive associations were identified between childhood Sirt1 and MVF during adulthood for both PORH (r=0.383; p=0.028) and Ach (r=0.420; p=0.026). Childhood concentrations of Sirt1 were also negatively associated with markers of oxidative stress in adulthood (8‐isoprostane, r=−0.384; p=0.036).CONCLUSIONNovel observations suggest that lower concentrations of Sirt1 during childhood are associated with cutaneous microvascular dysfunction in adulthood. Different mechanisms including elevated oxidative stress may explain the observed premature vascular dysfunction. Given the complexity of the mechanisms, additional research is needed to determine the specific mediators involved in the reduced microvascular function observed in this cohort.Support or Funding InformationSupported in part by NIH/NHLBI P01HL069999 (JSP, RAH) and 16POST31080031 (PRM).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.