Mechanisms of oxidative stress in human aortic aneurysms — Association with clinical risk factors for atherosclerosis and disease severity

Abstract

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2•−) production in human AAA.Methods and resultsAAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2•− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size.ConclusionsIncreased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.

Intermedin 1− 53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

“…4,7,22 Our data and that of others showed that in situ ROS generation was greatest in medial cells or adventitia fibroblasts in Ang Ⅱ-induced AAA.…”

“…2 The hallmark pathological features of AAA are typified by intense oxidative stress, inflammation, matrix degradation, and apoptosis of vascular smooth muscle cells (VSMCs). 3 Reactive oxygen species (ROS) are thought to be a common link between inflammation, matrix degradation, and VSMC apoptosis, 4,5 so reducing ROS may be a therapeutic target of AAA. In animal models of AAA, genetic and pharmacological inhibition of ROS suppressed aneurysm formation.…”

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

“…Based on these observations, we concluded that VPO1 modulates VSMC phenotypic switch through H 2 O 2 /VPO1/HOCl/ERK1/2 signaling pathway, which plays a key role in the formation of AAA. Oxidative stress has been described as an important signaling pathway in human AAA development and animal models of AAA 21, 22. The specific identity of reactive oxygen species that is responsible for the development of aortic dilation remains elusive 4, 23, 24.…”

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

“…Nox5 is expressed in all vascular cell types, including endothelial cells, VSMCs, and perivascular adventitial fibroblast,12, 14, 24 and plays a role in angiotensin II (Ang II)‐ and endothelin‐1 (ET‐1)‐mediated redox signaling 25. Nox5 expression is increased in human atherosclerotic and aneurysm lesions26, 27 and in kidneys from diabetic patients 28. We demonstrated that mice expressing human Nox5 in a podocyte‐specific manner exhibit podocyte injury and renal dysfunction,28 and that human Nox5 expression in mesangial cells causes renal fibrosis, nephropathy, and exacerbated atherosclerosis in diabetic mice 29.…”