Endothelial Dysfunction and Oxidant Status in Pediatric Patients with Hemoglobin E-β Thalassemia

Kukongviriyapan, Veerapol; Somparn, Nuntiya; Senggunprai, Laddawan; Prawan, Auemduan; Kukongviriyapan, Upa; Jetsrisuparb, Arunee

doi:10.1007/s00246-007-9107-x

Cited by 52 publications

(31 citation statements)

References 28 publications

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“…Implications for Pathophysiology-HbE/␤-thalassemia patients manifest endothelial dysfunction (95). Endothelial dysfunction is associated with reduced production of NO through the endothelial NOS pathway and increased production of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

Roche

Malashkevich

Balazs

et al. 2011

Journal of Biological Chemistry

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Hemoglobin (Hb) E (␤-Glu26Lys) remains an enigma in terms of its contributions to red blood cell (RBC) pathophysiological mechanisms; for example, EE individuals exhibit a mild chronic anemia, and HbE/␤-thalassemia individuals show a range of clinical manifestations, including high morbidity and death, often resulting from cardiac dysfunction.The purpose of this study was to determine and evaluate structural and functional consequences of the HbE mutation that might account for the pathophysiology. Functional studies indicate minimal allosteric consequence to both oxygen and carbon monoxide binding properties of the ferrous derivatives of HbE. In contrast, redoxsensitive reactions are clearly impacted as seen in the following: 1) the ϳ2.5 times decrease in the rate at which HbE catalyzes nitrite reduction to nitric oxide (NO) relative to HbA, and 2) the accelerated rate of reduction of aquometHbE by L-cysteine (L-Cys). Sol-gel encapsulation studies imply a shift toward a higher redox potential for both the T and R HbE structures that can explain the origin of the reduced nitrite reductase activity of deoxyHbE and the accelerated rate of reduction of aquometHbE by cysteine. Deoxy-and CO HbE crystal structures (derived from crystals grown at or near physiological pH) show loss of hydrogen bonds in the microenvironment of ␤Lys-26 and no significant tertiary conformational perturbations at the allosteric transition sites in the R and T states. Together, these data suggest a model in which the HbE mutation, as a consequence of a relative change in redox properties, decreases the overall rate of Hb-mediated production of bioactive NO.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

Roche

Malashkevich

Balazs

et al. 2011

Journal of Biological Chemistry

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“…In summary, increased platelet activation in thalassemia is a consequence of combined factors, including oxidative stress, PS-exposed erythrocytes, high amounts of circulating microparticles, nitric oxide scavenging by cell-free hemoglobin (180), and endothelial dysfunction (99). Moreover, cell-free hemoglobin can activate platelets through the action of adenosine diphosphate-bound hemoglobin (79).…”

Section: Fig 2 Hbe Acts As a Bmentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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“…Accumulation of nitrate and nitrite, the end products of NO metabolism used as indices of nitric oxide synthase (NOS) activity, was measured in plasma using a previously described method (Kukongviriyapan et al 2008). In brief, plasma samples were deproteinized by ultrafiltration using centrifugal concentrators (NanosepTM, Pal Filtron, USA).…”

Section: Assay Of Nitrate/nitritementioning

confidence: 99%

Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with l-NAME-induced hypertension

Nakmareong

Kukongviriyapan

Pakdeechote

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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140

128

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Inhibition of nitric oxide synthesis with N ( ω )-nitro-L-arginine methyl ester (L-NAME) induces marked hypertension and oxidative stress. Curcumin (CUR) has been shown strong antioxidant property. Tetrahydrocurcumin (THU), a major metabolite of CUR, possesses several pharmacological effects similar to CUR; however, it is less studied than CUR. We investigated whether CUR and THU could prevent vascular dysfunction and inhibit development of hypertension in L-NAME-treated rats. Male Sprague-Dawley rats were administered with L-NAME (50 mg/kg/day) in drinking water for 3 weeks. CUR or THU (50 and 100 mg/kg/day) was fed to animals simultaneously with L-NAME. L-NAME administration induced increased arterial blood pressure and elevated peripheral vascular resistance accompanied with impaired vascular responses to angiotensin II and acetylcholine. CUR and THU significantly suppressed the blood pressure elevation, decreased vascular resistance, and restored vascular responsiveness. The improvement of vascular dysfunction was associated with reinstating the marked suppression of eNOS protein expression in the aortic tissue and plasma nitrate/nitrite. Moreover, CUR and THU reduced vascular superoxide production, decreased oxidative stress, and increased the previously depressed blood glutathione (GSH) and the redox ratios of GSH in L-NAME hypertensive rats. The antihypertensive and some antioxidant effects of THU are apparently more potent than those of CUR. This study suggests that CUR and THU prevented the development of vascular dysfunction induced by L-NAME and that the effects are associated with alleviation of oxidative stress.

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Endothelial Dysfunction and Oxidant Status in Pediatric Patients with Hemoglobin E-β Thalassemia

Cited by 52 publications

References 28 publications

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with l-NAME-induced hypertension

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