Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

Ferreiro, Carlos; Chagas, Antônio Carlos Palandri; Carvalho, Maria Helena Catelli de; Dantas, Ana Paula; Jatene, Marcelo Biscegli; Souza, Luiz Carlos Bento de; Luz, Protásio Lemos da

doi:10.1161/01.cir.103.18.2272

Cited by 85 publications

(51 citation statements)

References 34 publications

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“…Increased circulating inflammatory mediators also accompanied raised plasma NO x levels, and cytokine-inducible NO synthase (NOS) expression has been described in pulmonary arteries and cardiac tissues of patients with flow-associated pulmonary hypertension and cyanotic congenital heart disease. 27,28 This represents a potentially important source of "high-output" NO production that may be associated with oxidative stress and the production of reactive NO species that attenuate the mobilization, function, and survival of EPCs. 29,30 Increasing evidence indicates that inflammation has a key role in the pathogenesis of PAH.…”

Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

et al. 2008

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Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34 + , CD34 + /AC133 + , CD34 + /KDR + , and CD34 + /AC133 + /KDR + progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

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Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

et al. 2008

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“…12 These data are in agreement with the study by Ferreiro et al showing that nitric oxide synthesis activity was blunted in patients with CCHD, suggesting that the endothelial function is impaired. 39 The endothelium may be damaged by the increased shear stress on the vessel wall caused by increased blood viscosity and/or by chronic hypoxemia in CCHD. 3 It has been speculated that in patients with primary pulmonary hypertension, damage to the endothelium leads to a decreased thrombomodulin level and to platelet activation.…”

Section: Endothelial Dysfunction In Cchdmentioning

confidence: 99%

Increased Thrombogenesity in Patients With Cyanotic Congenital Heart Disease

Kajimoto

Nakazawa

Murasaki

et al. 2007

Circ J

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yanotic congenital heart disease (CCHD) is associated with an increased risk of stroke and thromboembolism. 1 A recent study using contrast-enhanced computed tomography revealed a high prevalence of pulmonary thrombosis in patients with Eisenmenger syndrome. 2 The precise mechanisms of the increased incidence of thromboembolism in patients with CCHD have not yet been determined, but endothelial dysfunction, hemostatic abnormalities and platelet activation may be underlying factors causing hypercoagulability and thromboembolism. [3][4][5] Platelets interact with endothelial cells, leukocytes and other platelets. 6 Intravascular thrombus formation is enhanced by thrombin, which activates the coagulation cascade, platelets and the formation of neutrophil/platelet conjugates. 6-8 P-selectin is an adhesion molecule found in the secretory granules of platelets and Weibel -Palade bodies of endothelial cells, and is mobilized to the plasma membrane on activation. 6,9,10 P-selectin expressed on platelets may be a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases. 11 Although P-selectin is likely to play an important role in the thrombus formation, 6,11 there have been only a few studies evaluating Pselectin in CCHD. 4,12,13 Thrombomodulin is expressed mainly on the surface of vascular endothelial cells and prevents blood clotting on the internal surface of vessels. Endothelial thrombomodulin is a key component of the protein C anticoagulant pathway that facilitates the activation of protein C by thrombin. 14 Therefore, thrombomodulin acts as an intrinsic anticoagulant barrier between the blood and the endothelium. The plasma thrombomodulin level was elevated in disseminated intravascular coagulation and atheromatous arterial disease. 15,16 It may initially increase with acute vascular injury but decrease with subsequent downregulation of its production during chronic vessel injury. Several reports have shown that reduced thrombomodulin enhances thrombus formation. 17,18,19 We hypothesized that the decreased expression of protein C and the increased expression of Pselectin on platelets due to a reduced thrombomodulin level may contribute to the formation of thrombi in patients with CCHD. To test this hypothesis, we measured plasma levels of thrombomodulin and protein C, and the expression of Pselectin on platelets in patients with CCHD. The plasma thrombin -antithrombin complex III (TAT) level was also measured to evaluate coaguability. Methods PatientsWe enrolled 35 patients with CCHD. The inclusion criterion was the presence of cyanosis due to right-to-left shunt in patients with congenital heart disease. The demography of the patients is summarized in Table 1. There were 19 men and 16 women, with a mean age of 13±11 years, ranging from 1 to 37 years. Twenty-five patients had undergone palliative operations (Balock-Taussig shunt or bidirectional Glenn). Eight patients underwent definitive operations (Fontan operation in 7 and Rastelli operation in 1), but the Circ J 2007; 71: 948...

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“…RT-PCR analysis of nitric oxide synthase (NOS) mRNA was performed as described by Ferreiro et al (8). Data are reported as means ± SD for rabbits that survived all stages of the study.…”

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confidence: 99%

Estrogen enhances vasoconstrictive remodeling after injury in male rabbits

Francisco

Dantas

Carvalho

et al. 2005

Braz J Med Biol Res

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The complete spectrum of estrogen vascular effects remains unclear. In particular, estrogen effects in the vascular response to profound injury in males have not been explored in detail. Therefore, we submitted 44 male New Zealand rabbits weighing 3.4 ± 0.6 kg to overdistention balloon injury of the right iliac artery. Rabbits were given 17ß-estradiol (5.45 µmol/day, sc) or vehicle for 7 days before and 14 days after injury, when the arteries were examined by postmortem histomorphometry. Arteriographic caliber was assessed in vivo at baseline and before sacrifice. On day 14 after injury, in vivo arteriographic caliber (baseline = 2.44 ± 0.43 mm) was decreased by 23.1 ± 0.1% in controls and by 44.5 ± 0.1% in estrogen-treated rabbits (P < 0.001). Neither the neointimal area nor the neointima/media area ratio changed after estrogen treatment. Collagen fraction was increased in the media and neointima of estrogen-treated rabbits vs control (1.38 ± 1.30 vs 0.35 ± 0.67, respectively, P = 0.01). Taken together, these findings suggest that estrogen increased negative vascular remodeling. Transcription of endothelial and inducible nitric oxide synthases (eNOS and iNOS) was analyzed by RT-PCR. eNOS mRNA expression was marginally increased after estrogen (P = 0.07) and injury. iNOS mRNA was increased 2-to 3-fold on day 14 after injury. With estrogen treatment, iNOS mRNA increased in uninjured arteries and exhibited a further 5.5-fold increase after injury. We concluded that estrogen increased lumen loss after balloon injury in male rabbits, likely by increased negative remodeling, which may be related to increased iNOS transcriptional rates.

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Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

Cited by 85 publications

References 34 publications

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Increased Thrombogenesity in Patients With Cyanotic Congenital Heart Disease

Estrogen enhances vasoconstrictive remodeling after injury in male rabbits

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