Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents Arterial Restenosis by Suppressing Vascular Smooth Muscle Cell Proliferation

Kim, Sun-Yee; Jeoung, Nam Ho; Oh, Chang Joo; Choi, Yoo‐Duk; Lee, Hyo‐Jeong; Kim, Han-Jong; Kim, Joon‐Young; Hwang, Jung Hwan; Tadi, Surendar; Yim, Yong‐Hyeon; Lee, Ki‐Up; Park, Keun-Gyu; Huh, Seung; Min, Ki-Nam; Jeong, Ki‐Heon; Park, Myoung Gyu; Kwak, Tae Hwan; Kweon, Gi Ryang; Inukai, Kouichi; Shong, Minho; Lee, Inkyu

doi:10.1161/circresaha.108.189837

Cited by 74 publications

(62 citation statements)

References 34 publications

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“…In support of this model is the finding that NQO1 Ϫ/Ϫ mice have a reduced ratio of NAD ϩ /NADH (36). Furthermore, it was lately shown that an increase in the NAD ϩ /NADH ratio induced by NQO1 results in AMPK activation (77), which subsequently sets the stage for further activation of PGC-1-by the AMPK-Sirt1 axis (21). Overall, our findings provide evidence for an additional layer of complexity in the regulation of PGC-1␣ expression and activity, which is mediated by NQO1 and the process of degradation by default (Fig.…”

Section: Discussionmentioning

confidence: 88%

The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

Adamovich

Shlomai

Tsvetkov

et al. 2013

Molecular and Cellular Biology

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b PGC-1␣ is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1␣ expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins-the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1␣ as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1␣ degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1␣ from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC-1␣ protection plays an important role in controlling both basal and physiologically induced PGC-1␣ protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC-1␣ expression and activity in regulating energy metabolism.

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Section: Discussionmentioning

confidence: 88%

The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

Adamovich

Shlomai

Tsvetkov

et al. 2013

Molecular and Cellular Biology

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“…Longer-term studies may also accentuate the contribution of very slow-eluting NP medicines. Beyond paclitaxel, the variety of antiproliferative treatments can be expanded to sirolimus and its analogs, newer developed drugs (40), and combination treatments.…”

Section: Discussionmentioning

confidence: 99%

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Chan

Rhee

Drum

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

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Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD. P ercutaneous coronary interventions (PCIs) using drug-eluting stents (DESs) are credited with significant reductions in vessel restenosis, due to the effective combination of a drug delivery system and mechanical scaffold (1). Despite the extensive clinical use of DESs to maintain vascular patency, not all coronary lesions are amenable to DES placement (2). In addition, DESs are associated with delayed endothelialization (3) and increased thrombogenicity (4, 5) that require extended antiplatelet treatment (6). In some cases, only bare metal stents (BMSs) may be applied, which lack the benefit of antirestenotic therapy and instead stimulate neointimal smooth muscle cell (SMC) proliferation (7,8).Nanomedicines may offer improvements to existing clinical treatments, including those for cardiovascular disorders (9, 10). Sub-100-nm organic nanoparticles (NPs) combine useful features of ultrasmall size (11, 12), surface modification (13), controlled drug release, biodegradability, and biocompatibility (14). Liposomal, polymeric, and albumin-based NPs have been formulated to improve drug solubility and deliver paclitaxel at doses higher than otherwise possible in circulation (15-17). Temporal control of drug delivery may facilitate endothelial healing after injury, as NPs may be used to deliver antiproliferative agents to the vascular wall when neointimal proliferation is most active, followed by complete degradation and clearance (18). Targeted NPs that bind to exposed antigens in injured arteries may help to achieve therapeutic doses at sites of injury, b...

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“…6) Several phytochemicals inhibiting oxidative stress have a beneficial effect in atherosclerosis and restenosis via their direct antioxidant actions. [7][8][9] Therefore, NQO-1 induction is likely to be of key importance in protecting against oxidative stress and suppressing atherosclerosis development. 7) Rho guanosine 5′-triphosphatases (GTPases) participate in cell adhesion, vesicle trafficking, cell cycle progression, gene expression and differentiation.…”

mentioning

confidence: 99%

“…[7][8][9] Therefore, NQO-1 induction is likely to be of key importance in protecting against oxidative stress and suppressing atherosclerosis development. 7) Rho guanosine 5′-triphosphatases (GTPases) participate in cell adhesion, vesicle trafficking, cell cycle progression, gene expression and differentiation. 10,11) Members of the Rho small GTPase and Rho kinase play a role in cardiovascular physiology 12,13) .…”

mentioning

confidence: 99%

The Small GTPases Regulate HMC05-Induced NQO-1 Expression with an Antioxidant Effect in Smooth Muscle Cells

Gum

Shin

Cho

2014

Biological & Pharmaceutical Bulletin

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Recently, Banhabackchulchunmatang (HMC05) has been implicated as a preventive and/or therapeutic candidate for cardiovascular diseases due to its inhibition of atherosclerosis lesions and its reduction of neointima formation. Knowledge of the mechanism of HMC05 in smooth muscle cells (SMC) is limited. However, SMC may be a potential target for HMC05 therapy because they are supported by the HMC05-mediated preservation of medial smooth muscle cell layers in pathogenic progression. Therefore, in the present study, we hypothesized that the effect of HMC05 is associated with reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase-1 (NQO-1) gene regulation, which precipitates an antioxidant effect in SMC. HMC05 significantly increased NQO-1 gene expression in a dose-and time-dependent manner. The reactive oxygen species-mediated toxicity that was generated by xanthine/xanthine oxidase was suppressed by HMC05. The knockdown of the NQO-1 gene abrogated the HMC05-mediated cytoprotection. Key words HMC05; isoprenylation; smooth muscle cell; reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase-1 (NQO-1) HMC05 is a water extract of Banhabackchulchunmatang that has been used for headaches and hypertension in traditional herbal medicines.1) A pilot study on the reduction of blood pressure by HMC05 was performed in a randomized, single-blind cross over trial.2) Recently, HMC05 was demonstrated to lead to potent inhibition of atherosclerosis lesions in high-fat and high-cholesterol-fed apoE-knockout mice, which was partially attributed to anti-inflammatory effects.3) Neointimal formation was also reduced by HMC05 via the inhibition of PDGF-mediated cellular signaling in balloon-injured carotid arteries.1) Therefore, HMC05 is a candidate for anti-atherosclerosis agent that has also been used as an herbal medicine. HMC05 shows no toxicity in humans and is standardized based on berberine and hesperidin. Interestingly, the medial smooth muscle cell layer was preserved via the administration of HMC05 at both balloon injury sites and atherosclerotic lesions; this indicates that smooth muscle cells (SMC) may be a promising target of HMC05 for the prevention of cardiovascular diseases.Reactive oxygen species (ROS) play a critical role in pathophysiology of vascular disease.4) ROS production in atherosclerotic lesions accelerates the migration of SMC from the media to the intima, which leads to the development of a fibrous thickened layer. SMC are therefore promising in targeting vascular redox signaling to prevent ROS. Reduced nicotinamide adenine dinucleotide phosphate (NAD(P) H): quinone oxidoreductase-1 (NQO-1) (EC 1.6.99.2) is a homodimeric flavoprotein that catalyzes a two-electron reduction of electrophilic quinone substrates.5) Inducible NQO-1 expression plays a major role as a potential O 2 − · scavenger in SMC. 6)Several phytochemicals inhibiting oxidative stress have a beneficial effect in atherosclerosis and restenosis via their direct antioxidant actions. 7-9) Th...

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Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents Arterial Restenosis by Suppressing Vascular Smooth Muscle Cell Proliferation

Abstract: Abstract-Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are important pathogenic mechanisms in atherosclerosis and restenosis after vascular injury. In this study, we investigated the effects of

Cited by 74 publications

References 34 publications

The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

The Small GTPases Regulate HMC05-Induced NQO-1 Expression with an Antioxidant Effect in Smooth Muscle Cells

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