Arteriosclerosis, Thrombosis, Vascular Biology
Session Title: Redox Signaling and Cardiovascular Disease
Abstract 16260: Glutaredoxin1 Preserves Endoplasmic Reticulum Stress Response in Aortic Endothelium in Aging
Abstract
Introduction/Hypothesis: Vascular aging is associated with endoplasmic reticulum (ER) stress and oxidative stress, which are closely linked mechanisms that predispose the elderly to cardiovascular diseases. Aging-related ER malfunction features impaired ER stress response also known as unfolded/misfolded protein response (UPR). Our previous studies showed glutaredoxin1 (Grx1), a potent thiol antioxidant that specifically remove oxidant-induced S-glutathionylation (PrS-SG) on protein thiols, plays a protective role in development of age-related metabolic syndrome, and aortic endothelial barrier dysfunction by hypercholesterolemia. PrS-SG of ER proteins is associated with ER stress. As such we hypothesize Grx1 preserves ER homeostasis in endothelial cells (ECs) during aging.
Methods and Results: In aortae from middle-aged Grx1-halpoinsufficient (Grx1+/-) and Grx1-/- mice (10-mo. old), the levels of Grx1 and BiP that is a sentinel marker of UPR activation, are decreased. Additionally, compared with age-matched wild-type (WT) group, major ER stress mediator CCAAT-enhancer-binding protein homologous protein (CHOP) and apoptosis executor cleaved caspase 3 are increased. These aortic changes in Grx1 deficient mice are coincident with an accumulation of PrS-SG, and are comparable to those in 22-mo-old WT mice. In human aortic ECs, Grx1 protein degradation is sensitive to ER stress caused by different stressors (e.g., glycosylation inhibitor tunicamycin, SERCA inhibitor thapsigargin, proteasome inhibitor MG132, S-glutathionylation inducer GSSG). Using mouse aortic ECs isolated Grx1 transgenic mice, we found upregulation of Grx1 by itself promotes BiP and CHOP expression, and confer resistance, especially to CHOP and apoptosis induced by thiol oxidative stress. In parallel with ER function regulated by Grx1, In EC-enriched lung tissues—but not livers— from 10-mo.-old Grx1-/- mice, phosphorylation of Akt and eNOS upon acute insulin stimulation is massively inhibited. Increasing Grx1 expression in human aortic ECs instigates Akt/eNOS/NO signaling.
Conclusions: Grx1 through preserving UPR improves vascular endothelial dysfunction during aging.
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