The Emerging Role of Gene Therapy in the Treatment of Cardiovascular Diseases

Barbato, Joel E.; Kibbe, Melina R.; Tzeng, Edith

doi:10.1080/10408360390250621

Cited by 12 publications

(4 citation statements)

References 293 publications

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“…NO is a vasoprotective molecule that has led to the development of therapies to enhance NO signaling, including dietary L-arginine,1415161718 drug-eluting stents,19 inhalational NO gas,2021 NOS gene therapy,2223 and recently arginase inhibition 1524. Unfortunately, gene therapy remains limited due to problems with the delivery system and vectors, as well as mutational concerns.…”

Section: Discussionmentioning

confidence: 99%

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

et al. 2016

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PurposePeroxynitrite plays a critical role in vascular pathophysiology by increasing arginase activity and decreasing endothelial nitric oxide synthase (eNOS) activity. Therefore, the aims of this study were to investigate whether arginase inhibition and L-arginine supplement could restore peroxynitrite-induced endothelial dysfunction and determine the involved mechanism.Materials and MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with SIN-1, a peroxynitrite generator, and arginase activity, nitrite/nitrate production, and expression levels of proteins were measured. eNOS activation was evaluated via Western blot and dimer blot analysis. We also tested nitric oxide (NO) and reactive oxygen species (ROS) production and performed a vascular tension assay.ResultsSIN-1 treatment increased arginase activity in a time- and dose-dependent manner and reciprocally decreased nitrite/nitrate production that was prevented by peroxynitrite scavenger in HUVECs. Furthermore, SIN-1 induced an increase in the expression level of arginase I and II, though not in eNOS protein. The decreased eNOS phosphorylation at Ser1177 and the increased at Thr495 by SIN-1 were restored with arginase inhibitor and L-arginine. The changed eNOS phosphorylation was consistent in the stability of eNOS dimers. SIN-1 decreased NO production and increased ROS generation in the aortic endothelium, all of which was reversed by arginase inhibitor or L-arginine. NG-Nitro-L-arginine methyl ester (L-NAME) prevented SIN-1-induced ROS generation. In the vascular tension assay, SIN-1 enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxant responses to acetylcholine that were reversed by arginase inhibition.ConclusionThese findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions.

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Section: Discussionmentioning

confidence: 99%

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

et al. 2016

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“…NO has multiple vasoprotective characteristics including endothelium-dependent vasorelaxation and restriction of vascular growth and inflammation [17]. Given the physiological significance of NO, NO-based therapeutics are under investigation, including dietary L-arginine [19][20][21], drug-eluting stents [22], inhalational NO gas [23,24], and eNOS gene therapy [25,26]. Here, we investigated the potential of THSG, an arginase inhibitor, as a novel NO-based therapeutic.…”

Section: Resultsmentioning

confidence: 99%

Arginase Inhibitor 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside Activates Endothelial Nitric Oxide Synthase and Improves Vascular Function

Nguyen

Won

et al. 2016

Planta Med

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Endothelial arginase constrains the activity of endothelial nitric oxide synthase by reducing nitric oxide bioavailability, which contributes to vascular diseases. During screening, we identified a novel compound from the rhizome of (Polygonaceae), 2,3,5,4'-tetrahydroxystilbene-2---D-glucoside (THSG), which inhibited arginase activity. THSG exhibited noncompetitive inhibition of arginase II and inhibited both arginases I and II in a dose-dependent manner. THSG-dependent arginase inhibition reciprocally increased nitric oxide production and decreased reactive oxygen species generation in aortic endothelia. These effects were associated with increased dimerization of endothelial nitric oxide synthase without changes in the protein expression levels of arginase I, arginase II, or endothelial nitric oxide synthase. In vascular tension assays, when aortic vessels from wild-type mice are incubated with THSG, responses to the nitric oxide-dependent vasorelaxant acetylcholine were augmented, but responses to an nitric oxide donor, sodium nitroprusside, were not affected. On the other hand, phenylephrine-dependent vasoconstriction was significantly retarded in THSG-treated vessels. In a high-cholesterol diet-fed atherogenic model mice (ApoE), THSG improved endothelial function by enhancement of the nitric oxide-cGMP pathway. Taken together, these results suggest that THSG may exert vasoprotective effects through augmentation of nitric oxide signaling by inhibiting arginase. Therefore, THSG may be useful in the treatment of vascular diseases that are derived from endothelial dysfunction, such as atherosclerosis.

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“…As NO has multiple vasoprotective characteristics, NO signaling-based therapeutics are under investigation such as dietary L-arginine [2425262728], drug-eluting stents [29], inhalational NO gas [3031], and NOS gene therapy [3233]. Unfortunately, oral L-arginine therapy produced controversial results [252728].…”

Section: Discussionmentioning

confidence: 99%

Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice

Nguyen

Ryoo

2017

Korean J Physiol Pharmacol

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Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered Ca2+/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease.

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The Emerging Role of Gene Therapy in the Treatment of Cardiovascular Diseases

Cited by 12 publications

References 293 publications

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

Arginase Inhibitor 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside Activates Endothelial Nitric Oxide Synthase and Improves Vascular Function

Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice

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