Nox4 NADPH oxidase contributes to smooth muscle cell phenotypes associated with unstable atherosclerotic plaques

Abstract

Plaque instability associated with acute coronary syndromes results in part from apoptosis and senescence of cells within the atherosclerotic (AS) lesion. Increased cellular oxidative stress has been proposed to contribute to plaque progression and changes in composition, leading to plaque instability. Our objective was to examine the role of NADPH oxidase in smooth muscle cell (SMC) phenotypes associated with an unstable plaque. Aortae were isolated from pre-lesion (8 weeks of age) and post-lesion (35 weeks of age) hypercholesterolemic mice (ApoE-/-/LDLR-/-, AS), and age-matched normal C57BL/6J mice. We observed an age-dependent increase in reactive oxygen species (ROS) in aorta from AS mice, with evidence for elevated ROS prior to lesion development. Whereas macrophage infiltration was restricted to the lesion, oxidized lipids extended beyond the plaque and into the vessel wall. Consistent with these findings, we observed dynamic changes in the expression of NADPH oxidases in AS vessels. Specifically, Nox1 expression was increased early and decreased with lesion progression, while induction of Nox4 was a late event. Nox2 and p22phox were elevated throughout lesion development. Similar to observations in aortae, SMCs isolated from the lesion of AS aortae had decreased Nox1 and increased Nox4 levels as compared to SMCs from normal mice. AS SMCs demonstrated increased generation of ROS, cell cycle arrest, evidence of senescence, and increased susceptibility to apoptosis. Overexpression of Nox4 in normal SMCs recapitulated the phenotypes of the AS SMCs. We conclude that increased expression of Nox4 in AS may drive SMC phenotypes that lead to the plaque instability and rupture responsible for myocardial infarction and stroke.

Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques

“…Interestingly patients with p47 phox hereditary deficiency had intermediate flow-mediated dilation and oxidative stress [28]. Changes in the NADPH oxidase system may contribute to smooth muscle cell phenotypes associated with unstable atherosclerotic plaques [29], and new therapeutic strategies for cardiovascular disease based on prevention of ROS production, include the development of less toxic and more selective NADPH oxidase inhibitors, allowing clarification of the role of each NADPH oxidase isoform and its potential use in clinical practice [16]. In this study we sought to investigate whether specific inhibition of NADPH oxidase decreases the progression of atheromatous plaques and reduces the pro-angiogenic mediators that lead to increase plaque risk for rupture.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…67 Expression of EBP50 is elevated in SMC after the angioplasty. 68 71 Vendrov et al 24 showed that while knockout of Ncf1 gene, encoding for p47 phox , an essential regulatory subunit of both Nox1 and Nox2, is protective in young Apoe −/− mice, the effect is lost in aged animals. 24 Areas of aortic atherosclerotic lesions, staining with DHE, levels of DNA oxidative damage, or macrophage infiltration were similar in aged Apoe −/− and Apoe…”

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

“…Importantly, the role of p53 in premature aging is evident from several mouse studies where persistent low-level activation and increased expression, by ROS signalling, telomere erosion or DNA damage, promotes senescence or irreversible cell cycle arrest [137–139]. In turn, vascular cell senescence is one proposed mechanism surrounding unstable atherosclerotic plaque progression [140]. The ability for p53 to control senescence is consistent with its function to restrain vascularized tumour development, but the precise role for maintenance of longevity requires further investigation [141].…”