Abstract
In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs) and tissues leading to structural and functional damage. We investigated glucose-induced aging in 3 types of ECs using senescence associated β-gal (SA β-gal) staining and cell morphology. Alterations of sirtuins (SIRTs) and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT) p300 was examined. Similar examinations were performed in tissues of diabetic animals. ECs in high glucose (HG) showed evidence of early senescence as demonstrated by increased SA β-gal positivity and reduced replicative capacities. These alterations were pronounced in microvascular ECs. They developed an irregular and hypertrophic phenotype. Such changes were associated with decreased SIRT (1–7) mRNA expressions. We also found that p300 and SIRT1 regulate each other in such process, as silencing one led to increase of the others’ expression. Furthermore, HG caused reduction in FOXO1’s DNA binding ability and antioxidant target gene expressions. Chemically induced increased SIRT1 activity and p300 knockdown corrected these abnormalities slowing aging-like changes. Diabetic animals showed increased cellular senescence in renal glomerulus and retinal blood vessels along with reduced SIRT1 mRNA expressions in these tissues. Data from this study demonstrated that hyperglycemia accelerates aging-like process in the vascular ECs and such process is mediated via downregulation of SIRT1, causing reduction of mitochondrial antioxidant enzyme in a p300 and FOXO1 mediated pathway.
Highlights
Diabetes and its complications account for significant morbidity and mortality throughout the world [1,2,3]
High Glucose Accelerates Aging Process in the endothelial cells (ECs) Suspecting that hyperglycemia accelerates aging, we first investigated whether glucose causes rapid aging process in the ECs as they are the primary target of diabetic vascular complications
We found aging changes in human microvascular EC (HMEC) starts as early as passage 1, as seen from positive b-gal staining in high glucose (HG) treated cells compared to NG treated cells where it appeared in passage 4
Summary
Diabetes and its complications account for significant morbidity and mortality throughout the world [1,2,3]. The major factor in the development of chronic diabetic complications is vascular EC dysfunction [4]. In response to high ambient glucose levels and subsequent oxidative stress, ECs elaborate large amount of vasoactive factors, growth factors and cytokines [6,7]. Such factors lead to increased production of extracellular matrix (ECM) proteins causing structural alterations [6,7,8]. Several such changes seen at the cellular and tissue level in diabetes are similar to the changes seen in normal aging process [9,10,11,12,13]
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