Thrombin and NAD(P)H Oxidase–Mediated Regulation of CD44 and BMP4-Id Pathway in VSMC, Restenosis, and Atherosclerosis

Vendrov, Aleksandr E.; Madamanchi, Nageswara R.; Hakim, Zeenat S.; Rojas, Mauricio; Runge, Marschall S.

doi:10.1161/01.res.0000221214.37803.79

Cited by 82 publications

(58 citation statements)

References 40 publications

(44 reference statements)

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“…While the specific factors initiating chronic inflammation in AAA remain unknown, enhanced vascular reactive oxygen species (ROS) production have been associated with chronic inflammation, atherosclerosis, and human abdominal aortic aneurysms [7,14,15]. ROS are a collection of oxygen-derived molecules such as NO and superoxide.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

et al. 2009

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Reactive oxygen species (ROS) are increased in human abdominal aortic aneurysms (AAA). NADPH oxidases are the predominant source of superoxide anion (O 2 − ) in the vasculature. Inducible nitric oxide synthase (iNOS) produces significant amount of nitric oxide (NO) during inflammatory processes. We hypothesized that ROS produced by NADPH oxidases and iNOS play an important role in aneurysm formation. We examined this hypothesis using selective blockade of NADPH oxidases and iNOS in a murine model of AAA. Mice, including C57BL/6, iNOS knockout (iNOS −/− ) mice, and its background matched control (C57BL/6), underwent AAA induction by periaortic application of CaCl 2 . Aortic diameter was measured at aneurysm induction and harvest. Beginning 1 week prior to aneurysm induction and continuing to aortic harvest 6 weeks later, one group of the C57BL/6 mice were treated with orally administered apocynin (NADPH oxidase inhibitor). Control mice were given water. The mean diameter and change in diameter of each group were compared with concurrent controls. Aortic levels of the NO metabolite, NO x N(NO 2 and NO 3 ), are significantly increased in CaCl 2 -treated wild type mice. INOS −/− mice are resistant to aneurysm induction. This is associated with reduced expression of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased production of NO x in the aortic tissues. Inhibition of NADPH oxidase by apocynin also blocked aneurysm formation. In conclusion, both iNOS deficiency and NADPH oxidase inhibition suppress aneurysm formation in association with decreased NO x levels. These studies suggest that both the NADPH oxidase and iNOS pathways contribute to ROS production and AAA development.

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Section: Discussionmentioning

confidence: 99%

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

et al. 2009

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“…Both TxA 2 (4,56) and NADPH oxidases (57,58) have an established role in atherogenesis and in the proliferative Fig. 9.…”

Section: Discussionmentioning

confidence: 99%

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Wilson

Cavanagh

Lesher

et al. 2009

Journal of Lipid Research

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Thromboxane A 2 (TxA 2 ), the principle product of platelet COX-1-dependent arachidonic acid metabolism, directs multiple pro-atherogenic processes via its receptor, TP. Oxidative challenge offsets TP degradation, a key component in limiting TxA 2 ʼs actions. Following TP activation, we observed cellular reactive oxygen species (ROS) generation coincident with increased TP expression. We examined the link between TP-evoked ROS and TP regulation. TP expression was augmented in TPa-transfected cells treated with a. This was reduced with a cellular antioxidant, N-acetyl cysteine, or two distinct NADPH oxidase inhibitors, diphenyleneiodonium and apocynin. Homologous upregulation of the native TP was also reduced in apocynintreated aortic smooth muscle cells (ASMCs) and was absent in ASMCs lacking an NADPH oxidase subunit (p47 2/2 ). TP transcription was not increased in IBOP-treated cells, indicating a posttranscriptional mechanism. IBOP induced translocation of TPa to the Golgi and reduced degradation of the immature form of the receptor. These data are consistent with a ROS-dependent mechanism whereby TP activation enhanced TP stability early in posttranscriptional biogenesis. Given the significant role played by TP and ROS in perturbed cardiovascular function, the convergence of TP on ROSgenerating pathways for regulation of TxA 2 -dependent events may be critical for cardiovascular disease.-Wilson,

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“…Neointima formation after vascular injury is a process of matrix reconstruction, which involves multiple growth factors and cytokines (24,25). Local renin-angiotensin system (RAS) participates in the process of restenosis, and plays a crucial role in its promotion (26,27).…”

Section: Discussionmentioning

confidence: 99%

Conditional expression of type 2 angiotensin II receptor in rat vascular smooth muscle cells reveals the interplay of the angiotensin system in matrix metalloproteinase 2 expression and vascular remodeling

Tao

Wang²,

Srivenugopal³

et al. 2009

Int J Mol Med

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Abstract. Angiotensin II is well implicated in neointimal proliferation and the resulting restenosis, however, the mechanisms involved remain unclear. The type 2 angiotensin II (AT2) receptor, largely unexpressed in the adult vasculature, however, appears at significant levels after vascular injury. To investigate the specific contribution of AT2 receptor and the interplay of the angiotensin system to neointima, we engineered rat vascular smooth muscle cells (VSMCs) to express the AT2 receptor in a tetracycline-regulated system. Several VSMC clones resistant to both hygromycin and G418 were selected, many of which showed high, but regulatable levels of AT2R expression within 48 h of doxycycline (Dox) exposure. In untransfected VSMCs and stable transfectants with no AT2R induction, Ang II significantly increased the expression of matrix metalloproteinase 2 (MMP-2), which is linked to neointimal growth. However, induction of AT2R by Dox addition markedly decreased MMP-2 levels (P<0.01) and this downregulation was further promoted by CV-11974, a specific antagonist of AT1 receptor. In contrast, the PD123319 compound, which selectively curtails the AT2 receptor, reversed the inhibition caused by CV-11974. We conclude that Ang II enhances the MMP-2 expression via AT1R, and that enforces AT2R inhibited the same. These data confirm that AT2R functions to downregulate the effects elicited by Ang II + AT1R signaling and point to the role of MMP and extracellular matrix in vascular injury. The findings provide fresh experimental approaches to prevent or control restenosis through transduction of VSMCs expressing optimal levels of AT2R.

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Thrombin and NAD(P)H Oxidase–Mediated Regulation of CD44 and BMP4-Id Pathway in VSMC, Restenosis, and Atherosclerosis

Cited by 82 publications

References 40 publications

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Conditional expression of type 2 angiotensin II receptor in rat vascular smooth muscle cells reveals the interplay of the angiotensin system in matrix metalloproteinase 2 expression and vascular remodeling

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