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Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping

Morgan, R. Garretta,b; Ives, Stephen J.a,b,f; Walker, Ashley E.a,b,c; Cawthon, Richard M.d; Andtbacka, Robert H.I.e; Noyes, Dirke; Lesniewski, Lisa A.a,b,c,f; Richardson, Russell S.a,b,c,f; Donato, Anthony J.a,b,c,f

doi: 10.1097/HJH.0000000000000157
ORIGINAL PAPERS: Ageing

Objective: Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension.

Methods and results: To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone γ-H2A.X (γ-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P = 0.29). Arterial telomere uncapping and P53/P21-induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P = 0.04 and P = 0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r = −0.02, P = 0.44 and r = 0.01, P = 0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r = 0.62, P < 0.001, ηp2 = 0.35). Finally, telomere uncapping was a significant predictor of hypertension status (P = 0.03), whereas mean telomere length was not (P = 0.68).

Conclusion: Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.

aGeorge E. Wahlen Department of Veterans Affairs Medical Center

bGeriatric Research Education and Clinical Center, Salt Lake City Geriatrics Research, Education, and Clinical Center (182), Veterans Administration Salt Lake City Health Care System

cDivision of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine

dDepartment of Human Genetics, Eccles Institute of Human Genetics

eDepartment of Surgery, University of Utah Health Sciences Center

fDepartment of Exercise and Sports Science, College of Health, University of Utah, Salt Lake City, Utah, USA

Correspondence to Anthony Donato, PhD, Division of Geriatrics, Department of Internal Medicine, University of Utah Veteran's Affairs Medical Center-SLC, GRECC Building 2, Rm 1D28, 500 Foothill Drive, Salt Lake City, UT 84148, USA. Tel: +1 801 582 1565x4331; fax: +1 801 585 3884; e-mail: tony.donato@utah.edu

Abbreviations: COPD, chronic obstructive pulmonary disease; CVDs, cardiovascular diseases; LDH, lactate dehydrogenase; LSD, least significance difference; P21, cyclin-dependent kinase inhibitor 1A; P53, tumor suppressor protein p53; pseudo R2, Nagelkerke's R2; r, Pearson correlation coefficient; S, single copy gene; T, telomeric DNA; WBCs, white blood cells; γ-H2, phosphorylated histone γ-H2A.X at serine 139; ηp2, partial eta squared

Received 25 October, 2013

Revised 14 December, 2013

Accepted 30 January, 2014

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