Abstract 130: Impact Of O-GlcNAcylation On Elastin Fragmentation In Aorta Of Aged Male And Female Fisher344 Rats

Abstract

O-GlcNAcylation is a regulatory mechanism involving the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins, playing a crucial role in cellular processes. Within vascular smooth muscle cells (VSMCs), O-GlcNAc impacts vascular function and is associated with cardiovascular risk. Vascular aging is characterized by changes in VSMCs, such as stiffness and loss of elasticity. Elastin, a component of the extracellular matrix, undergoes fragmentation during aging, triggering detrimental cascades and damage to end-organs. This study explores the correlation between O-GlcNAc and elastin fragmentation as a hallmark of aging. Specifically, we hypothesized that higher levels of O-GlcNAc induces fragmentation. Male and female Fisher 344 rats were evaluated at 3-(3M) and 16-month-old (16M). Thoracic aortas were isolated and strain/stress was measured with a tissue puller (DMT ® ), and systolic blood pressure (SBP) was measured in the carotid artery. O-GlcNAc levels, elastase expression and activity, and elastin fragmentation were assessed using Western blot, immunofluorescence, and histology. Data were analyzed using Two-way ANOVA-Tukey post-hoc (p<0.05). Results showed an age-related increase in blood pressure with the SBP in 16M males ~30 mmHg higher than in 3M (87±3 vs. 117±4). In females, there was a modest increase of about 16 mmHg in 16M than 3M (83±4 vs. 99±4). Aortic thickness increased in 16M male (3M 99±4 vs. 16M 114±3) and female (3M 99±3 vs. 16M 123±3) compared to 3M, but no sex difference was observed. The number of fragmented elastin fibers/cm of aorta was higher in 16M females (7±3) than 3M (2±1) and the elastase activity is 40% higher in aorta and serum of 16M females.Functionally, the aorta of 3M male rats, but not 16 M, exhibited higher strain/stress than age-matched females (3M male 2.5±0.9 vs. female 1.6±0.6; 16M male 5.1±0.9 vs. female 4.6±0.6). Interestingly, aged females and males presented higher levels of O-GlcNAc, and pharmacological induction of O-GlcNAc using Thiamet G (1uM) increased aortic stiffness and elastin fragmentation in 3M male rats (2.1±0.9 vs. 3.6±0.9). These findings suggest that O-GlcNAc contribute to aortic stiffness and blood pressure during aging, possibly through inducing elastin fragmentation.