Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis.

Shears, Larry L.; Kawaharada, Nobuyoshi; Tzeng, Edith; Billiar, Timothy R.; Watkins, Simon C.; Kovesdi, Imre; Lizonova, Alena; Pham, Si M.

doi:10.1172/jci119736

Cited by 234 publications

(135 citation statements)

References 38 publications

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“…These experimental data are corroborated by observations in human transplant patients in whom eNOS immunoreactivity has been shown to be gradually lost, and this loss of eNOS gene expression is associated with coronary endothelial dysfunction (64). Similarly, inhibition of inducible nitric oxide synthase (iNOS) in aortic allograft, or aortic transplantation in iNOS knock-out mice, significantly increases allograft vasculopathy (65,66). Conversely, enhanced expression of iNOS by gene transfer techniques completely prevents the vasculopathy (65).…”

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 57%

“…Similarly, inhibition of inducible nitric oxide synthase (iNOS) in aortic allograft, or aortic transplantation in iNOS knock-out mice, significantly increases allograft vasculopathy (65,66). Conversely, enhanced expression of iNOS by gene transfer techniques completely prevents the vasculopathy (65). However, under conditions of inadequate substrate (L-arginine), NO is not produced, but instead, superoxide anion (O2 .− ) is generated.…”

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 99%

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The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 57%

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 99%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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“…The potential effects of iNOS in atherosclerosis have clinical implications beyond a molecular mechanism of atherogenesis as well. Gene transfer of iNOS to injured vascular segments reduces neointima formation in normocholesterolemic animals, 25 providing impetus for studies involving gene transfer of iNOS in patients. Thus, a possible involvement of iNOS in the development of atherosclerotic lesions has important clinical implications.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

et al. 2001

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Background-Inducible nitric oxide synthase (iNOS) is expressed by leukocytes and smooth muscle cells in atherosclerotic lesions. To test whether NO produced by iNOS deficiency affects atherosclerosis, we studied apoE/iNOS-double knockout (dKO) and apoE-knockout (KO) control animals fed a "Western-type" diet. Methods and Results-After 16 weeks of Western-type diet, the aortic lesion area in apoE/iNOS-dKO males and females was significantly reduced, by 22% and 21%, respectively, compared with apoE-KO males and females. This effect was more pronounced after 24 weeks of Western-type diet, after which lesion formation in male and female dKO mice was reduced by 38% and 40%, respectively. Plasma levels of lipoperoxides in apoE/iNOS-dKO mice (2.0Ϯ0.23 mol/L) were significantly lower than in apoE-KO control animals (3.2Ϯ0.44 mol/L; Pϭ0.02). To test whether substrate deficiency plays a role in the proatherogenic actions of iNOS, we administered L-arginine to apoE-KO animals for 16 and 24 weeks. L-Arginine treatment did not affect lesion formation in apoE-KO animals fed a Western-type diet. Conclusions-Genetic deficiency of iNOS decreases diet-induced atherosclerosis and lowers plasma levels of lipoperoxides, a marker for oxidative stress, in apoE-KO animals. Reduction in iNOS-mediated oxidative stress could partly explain protection from lesion formation in dKO animals.

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“…Indeed, inhibition or deficiency of iNOS, particularly early after transplantation, may lead to an increase in allograft intimal thickening. 59,60 It therefore appears all the more likely that the effect of iNOS expression is dependent on the milieu in which it occurs and may be altered by other enzymes and their products.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 Is Widely Expressed in Atherosclerotic Lesions Affecting Native and Transplanted Human Coronary Arteries and Colocalizes With Inducible Nitric Oxide Synthase and Nitrotyrosine Particularly in Macrophages

Baker

Hall

Evans

et al. 1999

ATVB

280

178

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Abstract-Inflammation appears to have a major role in the development of atherosclerotic lesions affecting native and transplanted coronary arteries. The subsequent risk of plaque rupture and acute ischemic events correlates with the degree of inflammation and may be modified by aspirin, an anti-inflammatory cyclooxygenase inhibitor. Cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) are involved in the inflammatory response via the rapid and exaggerated production of prostanoids and nitric oxide, both of which may have proatherosclerotic effects. These effects may be mediated by the formation of peroxynitrite in the case of nitric oxide and involve "cross talk" between the two enzyme systems. This study aimed to investigate native and transplant atherosclerosis for the presence and distribution of Cox-2 and iNOS. Immunocytochemical studies were performed on atherosclerotic lesions from patients with native (nϭ12) and transplant (nϭ5) coronary disease by using antibodies to Cox-2, iNOS, and nitrotyrosine (an indicator of peroxynitrite production). Control tissue was obtained from unused donor hearts and at the time of autopsy. Cox-2 and iNOS colocalized predominantly in macrophages/foam cells in both types of atherosclerosis. Cox-2 expression was also detected in medial smooth muscle cells and endothelial cells, including those of the vasa vasorum. Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages. Cox-2 and iNOS are coexpressed in native and transplant atherosclerosis, possibly allowing for interaction between the enzymes and suggesting an alternative mechanism for the benefits of aspirin via inhibition of Cox-2 activity.

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Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis.

Cited by 234 publications

References 38 publications

The Role of Viruses in Cardiac Allograft Vasculopathy

The Role of Viruses in Cardiac Allograft Vasculopathy

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

Cyclooxygenase-2 Is Widely Expressed in Atherosclerotic Lesions Affecting Native and Transplanted Human Coronary Arteries and Colocalizes With Inducible Nitric Oxide Synthase and Nitrotyrosine Particularly in Macrophages

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