In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
Abstract:
Diabetes mellitus is a prominent risk factor of coronary microvascular disease (CMD) and the comorbidity of CMD in diabetic patients leads to an increasing occurrence of cardiac mortality. Increased protein O -linked β-N-acetylglucosaminylation ( O -GlcNAcylation), a post-translational modification of proteins, is implicated in the development of vascular complications in diabetes. Therefore, we investigated the molecular mechanisms in which excess protein O -GlcNAcylation advances the progression of CMD in diabetes through coronary endothelial cell dysfunction. We hypothesize that excess protein O -GlcNAcylation will up-regulate p53 which will induce the development of CMD. We had conducted in vivo and in vitro experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic mouse model, and endothelial cell-specific O -GlcNAcase (OGA, a regulatory enzyme that catalyzes the removal of O- GlcNAc from proteins)-overexpressing TH mice. We found that compared to control mice, TH mice exhibited a decrease in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function), reduced capillary density, and increased endothelial cell apoptosis in the left ventricle. In addition, TH mice showed a significant increase of p53 protein expression in mouse coronary endothelial cells (MCECs) compared to control mice. Moreover, overexpression of OGA lowered protein O -GlcNAcylation and decreased p53 levels in MCECs. p53 inhibition with pifithrin-α restoratively increased CFVR and cardiac contractility in TH mice. From this data, we conclude OGA overexpression lowers p53 expression levels and thus attenuates endothelial cell apoptosis and restores CFVR and cardiac function in diabetes. The downregulation of p53 through OGA overexpression could be a potential therapeutic target for CMD in diabetic patients.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.142.suppl_3.14425
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
1466401-X
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