Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation

Leyen, Heiko E. von der; Dzau, Victor J.

doi:10.1007/978-3-642-57077-3_25

Cited by 7 publications

(7 citation statements)

References 69 publications

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“…The β‐blocker nebivolol, which provides vasodilation through stimulation of the L‐arginine/NO pathway, demonstrated NO‐dependent benefits in reducing arterial stiffness in sheep 114 . In addition, NOS gene manipulation is a promising approach currently in preliminary stages of development 115 . The clinical utility of these therapies may increase as the precise mechanisms of NO bioactivity in cardiac health and disease become more clearly defined.…”

Section: No‐targeted Treatments In Cardiac Diseasementioning

confidence: 99%

Nitric Oxide in the Pathogenesis of Cardiac Disease

Raij

2006

J of Clinical Hypertension

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Endothelial dysfunction is characterized by a vasoconstrictive and prothrombotic state in the vasculature; it plays a role in all stages of cardiac disease and is a significant independent predictor of cardiovascular outcomes. Nitric oxide (NO) performs multiple biologic activities in the endothelium, including vasodilation and antithrombotic actions. Reduced NO bioactivity is a major component of endothelial dysfunction. Impaired NO bioactivity is an important factor in the pathogenesis of atherosclerosis and in the metabolic syndrome. The functions of NO bioactivity in the heart go well beyond those in the endothelium, as all 3 NO synthase (NOS) isoforms—endothelial NOS, neuronal NOS, and inducible NOS—are expressed in cardiac myocytes and mediate systolic, diastolic, and chronotropic cardiac functions. Impairment of NO bioactivity is a pathogenic factor in various forms of cardiac disease. Although these findings support the potential use of NO‐targeted therapies for treatment of cardiac disease, the complexities of the biologic actions of NO in the vasculature and heart are such that development of therapies is still largely in the preliminary stages.

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Section: No‐targeted Treatments In Cardiac Diseasementioning

confidence: 99%

Nitric Oxide in the Pathogenesis of Cardiac Disease

Raij

2006

J of Clinical Hypertension

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“…Of these candidate genes, eNOS is attractive not only because of its ability to promote smooth muscle cell (SMC) relaxation via activation of soluble guanylate cyclase but also because of other properties, including the ability to inhibit SMC proliferation, migration, and matrix production (15). NO also has been demonstrated to have antithombotic activity by preventing platelet aggregation and has antiinflammatory and immunoregulatory properties (15, 16). These observations suggest that the eNOS gene is an ideal target for genetic therapy of PH and its use in the studies described here are mainly to show the therapeutic potential of the gene delivery approach.…”

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confidence: 99%

Sleeping Beauty‐mediated eNOS gene therapy attenuates monocrotaline‐induced pulmonary hypertension in rats

Liu

Visner

et al. 2006

FASEB j.

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Pulmonary hypertension (PH) is a life-threatening disorder with high mortality rates and limited treatment options. Gene therapy is an alternative treatment strategy, yet viral vectors have inherent disadvantages including immune activation. The Sleeping Beauty (SB) transposon is a nonviral method of gene delivery that overcomes some of these drawbacks. A SB-based transposon harboring a constitutively active endothelial nitric oxide synthase (eNOS) gene was administered to Sprague-Dawley rats via tail vein injection using the carrier polyethylenimine. Two days after transposon delivery, monocrotaline (MCT) was administered to induce PH. Hemodynamic, histological, and molecular measurements were performed four weeks later. Animals coinjected with transposase showed a significant reduction in pulmonary arterial pressure (PABP, 31.67+/-6.03 mmHg, P<0.01), an attenuation of right ventricle (RV) to whole heart (WH) wt ratios (0.227+/-0.0252, P<0.05) and a decrease in the pulmonary vessel wall thickness index (36.87%, P<0.001), compared with those animals receiving the eNOS transposon and a nonfunctional transposase (PABP 44.33+/-4.04 mmHg; RV/WH ratio 0.280+/-0.01; wall thickness index 62.14%) or control animals receiving MCT injection alone (PABP 49.67+/-3.22 mmHg; RV/WH ratio 0.290+/-0.0265; wall thickness index 71.99%). The physiological improvements correlated with therapeutic gene expression, suggesting that transposon-based genetic approaches have utility in the treatment of PH.

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“…Activated macrophages and monocytes are known to express iNOS and produce NO under many inflammatory conditions including cardiovascular disorders (5,11,26,33,45). On the other hand, although most studies on portal hypertension have focused on the mechanisms and pathways through which eNOS activity is altered in the development of circulatory dysfunction (see Introduction), some studies have demonstrated the importance of iNOS in hyperdynamic circulation of liver cirrhosis (3,9,24,27,46).…”

Section: Discussionmentioning

confidence: 99%

iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats

Kajita

Murata

Horiguchi

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Portal hypertension, a major complication of cirrhosis, is caused by both increased portal blood flow due to arterial vasodilation and augmented intrahepatic vascular resistance due to sinusoidal constriction. In this study, we examined the possible involvement of resident macrophages in the tone regulation of splanchnic blood vessels using bile duct ligated (BDL) portal hypertensive rats and an in vitro organ culture method. In BDL cirrhosis, the number of ED2-positive resident macrophages increased by two- to fourfold in the vascular walls of the mesenteric artery and extrahepatic portal vein compared with those in sham-operated rats. Many ED1-positive monocytes were also recruited into this area. The expression of inducible nitric oxide (NO) synthase (iNOS) mRNA was increased in the vascular tissues isolated from BDL rats, and accordingly, nitrate/nitrite production was increased. Immunohistochemistry revealed that iNOS was largely expressed in ED1-positive and ED2-positive cells. We further analyzed the effect of iNOS expression on vascular smooth muscle contraction using an in vitro organ culture system. iNOS mRNA expression and nitrate production significantly increased in vascular tissues (without endothelium) incubated with 1 μg/ml lipopolysaccharide (LPS) for 6 h. Immunohistochemistry indicated that iNOS was largely expressed in ED2-positive resident macrophages. α-Adrenergic-stimulated contractility of the mesenteric artery was greatly suppressed by LPS treatment and was restored by N(G)-nitro-L-arginine methyl ester (NO synthase inhibitor); in contrast, portal vein contractility was largely unaffected by LPS. Sodium nitroprusside (NO donor) and 8-bromo-cGMP showed greater contractile inhibition in the mesenteric artery than in the portal vein with decreasing myosin light chain phosphorylation. In the presence of an α-adrenergic agonist, the mesenteric artery cytosolic Ca(2+) level was greatly reduced by sodium nitroprusside; however, the portal vein Ca(2+) level was largely unaffected. These results suggest that the induction of iNOS in monocytes/macrophages contributes to a hypercirculatory state in the cirrhosis model rat in which the imbalance of the responsiveness of visceral vascular walls to NO (mesenteric artery >> portal vein) may account for the increased portal venous flow in portal hypertension.

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Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation

Cited by 7 publications

References 69 publications

Nitric Oxide in the Pathogenesis of Cardiac Disease

Nitric Oxide in the Pathogenesis of Cardiac Disease

Sleeping Beauty‐mediated eNOS gene therapy attenuates monocrotaline‐induced pulmonary hypertension in rats

iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats

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