NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase

Gunnett, Carol A.; Lund, Donald D.; Chu, Yi; Brooks, Robert; Faraci, Frank M.; Heistad, Donald D.

doi:10.1161/hq0801.093509

Cited by 55 publications

(55 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study demonstrated that iNOS knock-out mice are resistant to endothelial dysfunction when made diabetic (16). Similarly when the iNOS gene was transferred to normal arteries, NO-dependent relaxation was impaired, suggesting endothelial dysfunction (17). These results strongly suggest a direct involvement of iNOS in endothelial dysfunction in diabetes.…”

Section: Discussionmentioning

confidence: 88%

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Nagareddy¹,

Xia²,

McNeill³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

139

View full text Add to dashboard Cite

(MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N- [3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction. inducible nitric oxide synthase; nitric oxide; cardiovascular abnormalities CHRONIC HYPERGLYCEMIA has been shown to directly affect the composition and structure of cardiac, vascular, and renal tissues, the progressive modification of which results in a deranged cardiovascular homeostasis (8). Cardiovascular depression, characterized by depressed mean arterial blood pressure (MABP), heart rate (HR), and attenuated pressor responses to vasoactive agents is one of the most notable manifestations of this derangement, particularly in animal models of Type 1 diabetes. Although the exact mechanisms by which diabetes contributes to cardiovascular depression are currently unknown, it is likely that hyperglycemia may initiate this abnormality through the activation of protein kinase C, increased activity of the polyol pathway, formation of nonenzymatic advanced glycosylation end products, oxidative stress, and/or possibly by induction of nitric oxide (NO) synthase (NOS) (19,42).The role of NO in the regulation of hemodynamics under hyperglycemic conditions has been controversial. Despite an impairment of endothelial function and reduced bioavailability of endothelium-derived NO, streptozotocin (STZ)-induced diabetic rats are not hypertensive but instead are normotensive or hypotensive (9,14,18,20,23,31,39,44). In addition, an increased dependence on a functional NO system at the onset of diabetes has been reported to prevent the development of hypertension in STZ diabetic rats (12). It has been suggested that increased NO synthesis m...

show abstract

Section: Discussionmentioning

confidence: 88%

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Nagareddy¹,

Xia²,

McNeill³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

139

View full text Add to dashboard Cite

show abstract

“…Previous studies in vessels exposed to inflammatory cytokines, mice rendered septic using injection of lipopolysaccharide (17) and iNOS gene transfer studies have all supported a role for iNOS-derived NO in causing vascular dysfunction (18,19). If one considers obesity to be an inflammatory condition analogous to low-grade sepsis, iNOS KO mice might be expected to be protected against classical endothelial dysfunction, as has been demonstrated to be the case in sepsis (17).…”

Section: Fig 6 Ros Production and Effect Of Catalase In Inos Ko Micmentioning

confidence: 92%

Inducible Nitric Oxide Synthase Has Divergent Effects on Vascular and Metabolic Function in Obesity

Noronha

Wheatcroft³

et al. 2005

Diabetes

143

109

View full text Add to dashboard Cite

Previous studies have suggested an involvement of inducible nitric oxide synthase (iNOS) in obesity, but the relation, if any, between this and mechanisms underlying endothelial dysfunction in obesity is unknown. We studied mice fed an obesogenic high-fat or standard diet for up to 8 weeks. Obesity was associated with elevated blood pressure; resistance to the glucoregulatory actions of insulin; resistance to the vascular actions of insulin, assessed as the reduction in phenylephrine constrictor response of aortic rings after insulin preincubation (lean ؊21.7 ؎ 11.5 vs. obese 18.2 ؎ 15.5%; P < 0.05); and evidence of reactive oxygen species (ROS)-dependent vasodilatation in response to acetylcholine in aortic rings (change in maximal relaxation to acetylcholine after exposure to catalase: lean ؊2.1 ؎ 6.0 vs. obese ؊15.0 ؎ 3.8%; P ‫؍‬ 0.04). Obese mice had increased expression of iNOS in aorta, with evidence of increased vascular NO production, assessed as the increase in maximal constriction to phenylephrine after iNOS inhibition with 1400W (lean ؊3.5 ؎ 9.1 vs. obese 42.1 ؎ 11.2%; P < 0.001). To further address the role of iNOS in obesity-induced vascular and metabolic dysfunction, we studied the effect of a high-fat diet in iNOS knockout mice (iNOS KO). Obese iNOS KO mice were protected against the development of resistance to insulin's glucoregulatory and vascular effects (insulindependent reduction in maximal phenylephrine response: obese wild-type 11.2 ؎ 15.0 vs. obese iNOS KO ؊20.0 ؎ 7.7%; P ‫؍‬ 0.02). However, obese iNOS KO mice remained hypertensive (124.0 ؎ 0.7 vs. 114.9 ؎ 0.5 mmHg; P < 0.01) and had evidence of increased vascular ROS production. Although these data support iNOS as a target to protect against the adverse effects of obesity on glucoregulation and vascular insulin resistance, iNOS inhibition does not prevent the development of raised blood pressure or oxidative stress. Diabetes 54: 1082-1089, 2005

show abstract

“…Adenoviral constructs containing inserts of the iNOS isoform gene had full-length (3,690 bp) mouse iNOS cDNA 19 (Gene Bank accession #M87039) inserted into an AdCMV vector following a CMV promoter between Not I and XhoI restriction sites. 20,21 The stock viral concentrations were as follows: Ad5CMVempty, 5.5 Â 10 10 PFU/ml; and Ad5CMViNOS, 2 Â 10 10 PFU/ml. The viruses were suspended in phosphate-buffered saline containing 3% sucrose, aliquoted to 20 ml portions and stored at À808C for further use.…”

Section: Adenovirusmentioning

confidence: 99%

Nitric oxide enhances collagen synthesis in cultured human tendon cells

Xia

Szomor

Wang

et al. 2005

Journal Orthopaedic Research

View full text Add to dashboard Cite

Collagen deposition is an important process that occurs during wound healing. We and others have shown that nitric oxide (NO) is important in tendon healing. The mechanisms whereby healing is enhanced are, however, undetermined. The aim of this study was to investigate whether NO could enhance collagen synthesis in cultured human tendon cells via exogenous NO and via an adenovirus containing the gene for inducible nitric oxide synthase (Ad-iNOS). Tendon cells from the torn edge of the tendons of patients undergoing rotator cuff repair surgery were cultured following collagenase digestion, and stimulated with exogenous NO (SNAP), transfected with Ad-iNOS, and treated with the NOS inhibitor, L-NMMA. Total protein and collagen synthesis were evaluated by 3 H-proline and collagenase sensitive 3 H-proline incorporation in human tendon cells. High doses of exogenous NO (SNAP) inhibited collagen synthesis. Lower doses enhanced total protein and collagen synthesis of the tendon cells. Ad-iNOS successfully transfected active iNOS into human tendon cells in vitro and also enhanced total protein and collagen synthesis of the tendon cells. The NOS inhibitor, L-NMMA, inhibited the effects of iNOS on the cells. Our studies show for first time that nitric oxide can enhance collagen synthesis in human tendon cells in vitro. These results may explain, in part, at least, the beneficial effects of NO donors in animal models and during the treatment of tendonopathies in human clinical trials. ß

show abstract

NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase

Cited by 55 publications

References 62 publications

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Inducible Nitric Oxide Synthase Has Divergent Effects on Vascular and Metabolic Function in Obesity

Nitric oxide enhances collagen synthesis in cultured human tendon cells

Contact Info

Product

Resources

About