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The correlation of IRE1? oxidation with Nox4 activation in aging-associated vascular dysfunction.

ABSTRACT: Oxidative stress attributable to the activation of a Nox4-containing NADPH oxidase is involved in aging-associated vascular dysfunction. However, the Nox4-induced signaling mechanism for the vascular alteration in aging remains unclear. In an aged aorta, the expression of Nox4 mRNA and protein by Nox family of genes was markedly increased compared with a young aorta. Nox4 localization mainly to ER was also established. In the aorta of Nox4 WT mice aged 23-24 months (aged), reactive oxygen species (ROS) and endoplasmic reticulum (ER)/oxidative stress were markedly increased compared with the counter KO mice. Furthermore, endothelial functions including eNOS coupling process and acetylcholine-induced vasodilation were significantly disturbed in the aged WT, slightly affected in the counter KO aorta. Consistently, in d-galactose-induced in vitro aging condition, ER-ROS and its associated ER Nox4 expression and activity were highly increased. Also, in chronic d-galactose-treated condition, IRE1? phosphorylation and XBP-1 splicing and were transiently increased, but IRE1? sulfonation was robustly increased in the aging Nox4 WT condition when compared to the counter KO condition. In vitro D-gal-induced aging study, the phenomenon were abrogated with Nox4 knock-down condition and was significantly decreased in GKT, Nox4 inhibitor and 4-PBA, ER chemical chaperone-treated human umbilical vein endothelial cells. The state of Nox4-based ER redox imbalance/ROS accumulation is suggested to determine the pathway "the UPR; IRE1? phosphorylation and XBP-1 splicing and the UPR failure; IRE1? cysteine-based oxidation, especially sulfonation, finally controlling aging-associated vascular dysfunction.

SUBMITTER: Lee HY

PROVIDER: S-EPMC7530295 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The correlation of IRE1α oxidation with Nox4 activation in aging-associated vascular dysfunction.

Lee Hwa-Young HY Kim Hyun-Kyoung HK Hoang The-Hiep TH Yang Siyoung S Kim Hyung-Ryong HR Chae Han-Jung HJ

Redox biology 20200914

Oxidative stress attributable to the activation of a Nox4-containing NADPH oxidase is involved in aging-associated vascular dysfunction. However, the Nox4-induced signaling mechanism for the vascular alteration in aging remains unclear. In an aged aorta, the expression of Nox4 mRNA and protein by Nox family of genes was markedly increased compared with a young aorta. Nox4 localization mainly to ER was also established. In the aorta of Nox4 WT mice aged 23-24 months (aged), reactive oxygen specie ...[more]

PMID: 33010578

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Project description:Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe(-/-) mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD.Both aged (16 months) Apoe(-/-) and Apoe(-/-)/p47phox(-/-) mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox(-/-) mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe(-/-) mice treated with MitoTEMPO and 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function.These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD.

Project description:AimsDiastolic dysfunction is common in geriatric heart failure. A reliable parameter to predict myocardium stiffness and relaxation under similar end-diastolic pressure is being developed. We propose a material and mathematical model for calculating myocardium stiffness based on the concept of linear correlation between [Formula: see text] and wedge pressure.Methods and resultsWe enrolled 919 patients (male: [Formula: see text][Formula: see text]). Compared with the younger population of controls (mean age: [Formula: see text] years; [Formula: see text]; male: [Formula: see text] [Formula: see text]), the elderly (mean age: [Formula: see text]; [Formula: see text]; male: [Formula: see text] [Formula: see text]) had a greater prevalence of hypertension, diabetes mellitus, and coronary artery disease (all [Formula: see text]). We collected their M-mode and 2-D echocardiographic volumetric parameters, intraventricular filling pressure, and speckle tracking images to establish a mathematical model. The feasibility of this model was validated. The average early diastolic velocity of the mitral annulus assessed using tissue Doppler imaging was significantly attenuated in the elderly ([Formula: see text]: [Formula: see text] vs. [Formula: see text]; [Formula: see text]) and corresponded to the higher estimated wedge ([Formula: see text]) pressure ([Formula: see text] vs. [Formula: see text]; [Formula: see text]) in that cohort. E (Young's modulus) was calculated to describe the tensile elasticity of the myocardium. With the same intraventricular filling pressure, E was significantly higher in the elderly, especially those with [Formula: see text] values [Formula: see text]. Compared with diastolic dysfunction parameters, E also presented sentinel characteristics more sensitive for detecting early myocardial relaxation impairment, which indicates stiffer myocardium in aging hearts.ConclusionOur material and geometric mathematical model successfully described the stiffer myocardium in aging hearts with higher intraventricular pressure. Additional studies that compare individual differences, especially in health status, are needed to validate its application for detecting diastolic heart failure.

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The correlation of IRE1? oxidation with Nox4 activation in aging-associated vascular dysfunction.

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The correlation of IRE1α oxidation with Nox4 activation in aging-associated vascular dysfunction.

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