High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway.
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.
Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Rokhsana
R
Mortuza
Shali
S
Chen
Biao
B
Feng
Subhrojit
S
Sen
Subrata
S
Chakrabarti
D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics; D056565:Sirtuin 2 / Q000235:genetics; D056566:Sirtuin 3 / Q000235:genetics; D037761:Sirtuins / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose; D024101:Mitochondrial Proteins; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3; D037761:Sirtuins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C085126:FOXO1 protein, human; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; C466093:SIRT3 protein, human; C525357:SIRT4 protein, human; C508544:SIRT5 protein, human; C516592:SIRT6 protein, human