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Arginase 1 regulates SIRT1 activity and endothelial senescence in diabetes (1051.1)
Author(s) -
Toque Haroldo,
Bhatta Anil,
Yao Lin,
Caldwell Ruth,
Caldwell R.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1051.1
Subject(s) - senescence , sirtuin 1 , arginase , medicine , endocrinology , diabetes mellitus , sirtuin , chemistry , downregulation and upregulation , biology , arginine , enzyme , biochemistry , nad+ kinase , amino acid , gene
Premature senescence in endothelial cells (EC) has emerged as a factor in vascular endothelial dysfunction (VED) during diabetes and other cardiovascular diseases. Diabetes‐induced VED involves elevated arginase (ARG) activity. Reduced levels/activity of sirtuin 1 (SIRT1, a histone deacetylase essential for EC self‐renewal and resistance to stressors) have been linked to premature senescence. We examined the roles of ARG and SIRT1 in diabetes‐induced premature EC senescence by studies using EC specific‐ARG1 knockout (KO) mice and bovine aortic and human coronary EC and WT mouse aorta transduced with ARG1 cDNA (24 hr) or exposed to high glucose (HG, 25 mM, 72 hr). We observed that diabetic or ARG1 transduced aorta exhibited premature EC senescence [measured as senescence‐associated β‐galactosidase (SA‐β‐gal) activity], decreases in SIRT1 activity/expression and VED accompanied by increases in ARG activity and reduced NO production. These effects were not seen in diabetic KO mice with EC specific deletion of ARG1. Furthermore, EC transduced with ARG1 or treated with HG showed marked decreases in SIRT1 activity and NO production which were accompanied by significant increases in activity of ARG and SA‐β‐gal. Hence, reducing ARG1 activity/expression preserves SIRT1 levels, maintains NO production and prevents premature EC senescence and thus has therapeutic potential in attenuating diabetes‐induced VED. Grant Funding Source : AHA Scientific Development Grant