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Proteomic profiling of endothelium-dependent vasodilation

Lind, Larsa; Sundström, Johana; Ärnlöv, Johanb,c; Ingelsson, Erikd,e,f

doi: 10.1097/HJH.0000000000001863

Objective: As endothelial dysfunction is an early event in atherosclerosis formation, we investigated if proteins previously related to cardiovascular disease also were related to endothelial function using a novel targeted proteomics approach.

Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 850–970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intra-arterial infusion of acetylcholine. Flow-mediated vasodilation (FMD) was investigated in the brachial artery by ultrasound. The same investigations were carried out in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 375–461, all aged 50 years). After strict quality control, 84 cardiovascular-related proteins measured by the proximity extension assay were studied in relation to EDV and FMD in PIVUS (discovery sample) and POEM (validation sample).

Results: Of the 15 proteins being significantly related to EDV in PIVUS (false discovery rate <0.025), seven could be replicated in POEM at nominal significance and same effect direction when adjusted for sex and storage time. Of those, only cathepsin D remained significant following further adjustment for traditional cardiovascular risk factors (beta, −0.08; 95% confidence interval, −0.16, −0.01; P = 0.033; change in ln-transformed EDV per 1-SD increase in protein level). No protein was significantly related to FMD.

Conclusion: Using a discovery/validation approach in two samples, our results indicate an inverse association between plasma cathepsin D levels and endothelial-dependent vasodilation.

aDepartment of Medical Sciences, Uppsala University, Uppsala

bSchool of Health and Social Studies, Dalarna University, Falun

cDivision of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

dDivision of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine

eStanford Cardiovascular Institute, Stanford University, Stanford, California, USA

fDepartment of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Correspondence to Lars Lind, MD, Department of Medical Sciences, University Hospital of Uppsala, 751 85 Uppsala, Sweden. Tel: +46 730502878; e-mail:

Abbreviations: EDV, endothelium-depedent vasodilation; EIDV, endothelium-indepedent vasodilation; FDR, false discovery rate; FMD, flow-mediated vasodiation; PEA, proximity extension assay; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; POEM, Prospective Investigation of Obesity, Energy and Metabolism

Received 23 April, 2018

Revised 1 June, 2018

Accepted 19 June, 2018

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