Cytoprotective effects of albumin, nitrosated or reduced, in cultured rat pulmonary vascular cells
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. AJP Lung Cellular and Molecular Physiology
(Impact Factor: 4.08).
03/2011; 300(4):L526-33. DOI: 10.1152/ajplung.00282.2010
S-nitrosoalbumin (SNO-Alb) has been shown to be an efficacious cytoprotective molecule in acute lung injury, as well as ischemia-reperfusion injury in heart and skeletal muscle. Nonetheless, limited information is available on the cellular mechanism of such protection. Accordingly, we investigated the protective effects of SNO-Alb [ and its denitrosated congener, reduced albumin (SH-Alb) ] on tert-butyl hydroperoxide (tBH)-mediated cytotoxicity in cultured rat pulmonary microvascular endothelial cells (RPMEC), as well as hydrogen sulfide (H(2)S)-mediated cytotoxicity in rat pulmonary artery smooth muscle cells (RPASMC). We noted that tBH caused a concentration-dependent necrosis in RPMEC, and pretreatment of RPMEC with SNO-Alb dose-dependently decreased the sensitivity of these cells to tBH. A component of SNO-Alb cytoprotection was sensitive to N(G)-nitro-L-arginine methyl ester and was associated with activation of endothelial nitric oxide synthase (eNOS), phenomena that could be reproduced with pretreatment with SH-Alb. Exogenous H(2)S caused concentration-dependent apoptosis in RPASMC due to activation of ERK1/2 and p38, as well as downregulation of Bcl-2. Pretreatment with SNO-Alb reduced H(2)S-mediated apoptosis in a concentration-dependent manner that was associated with SNO-Alb-mediated inhibition of activation of ERK1/2 and p38. Pretreatment with SNO-Alb reduced toxicity of 1 mM sodium hydrosulfide in an N(G)-nitro-L-arginine methyl ester-sensitive fashion in RPASMC that expressed gp60 and neuronal NOS and was capable of transporting fluorescently labeled SH-Alb. Therefore, SNO-Alb is cytoprotective against models of oxidant-induced necrosis (tBH) and inhibitors of cellular respiration and apoptosis (H(2)S) in both pulmonary endothelium and smooth muscle, respectively, and a component of such protection can be attributed to a SH-Alb-mediated activation of constitutive NOS.
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ABSTRACT: Smooth muscle cell (SMC) proliferation has been accepted as a common event in the pathophysiology of vascular diseases, including atherogenesis and intimal hyperplasia. Delivery of the nitric oxide synthase (NOS) substrate l-arginine, pharmacological nitric oxide (NO) donors, NO gas or overexpression of NOS proteins can inhibit SMC proliferation and reduce the injury responses within the blood vessel wall. Although commercial development of NO donors that attempt to provide exogenous delivery of NO has accelerated over the last few years, none of the currently available products can provide controlled, sustained, time-tunable release of NO. Nitrosamine-based NO donors, prepared in our laboratory, present a unique and innovative alternative for possible treatments for long-term NO deficiency-related diseases, including atherosclerosis, asthma, erectile dysfunction, cancer, and neurodegenerative diseases. A family of secondary amines prepared via nucleophilic aromatic displacement reactions could be readily N-nitrosated to produce NO donors. NO release takes place in three distinct phases. During the initial phase, the release rate is extremely fast. In the second phase, the release is slower and the rate remains essentially the same during the final stage. These compounds inhibited up to 35% human aortic smooth muscle cell proliferation in a concentration-dependent manner.
Chemical Biology & Drug Design 07/2011; 78(4):527-34. DOI:10.1111/j.1747-0285.2011.01174.x · 2.49 Impact Factor
Available from: Ufuk Cakatay
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ABSTRACT: Human serum albumin, a negative acute phase reactant and marker of nutritive status, presents at high concentrations in plasma. Albumin has always been used in many clinical states especially to improve circulatory failure. It has been showed that albumin is involved in many bioactive functions such as regulation of plasma osmotic pressure, binding and transport of various endogenous or exogenous compounds, and finally extracellular antioxidant defenses. Molecules like transferrin, caeruloplasmin, haptoglobin, uric acid, bilirubin, alpha-tocopherol, glucose, and albumin constitute extracellular antioxidant defenses in blood plasma but albumin is the most potent one. Most of the antioxidant properties of albumin can be attributed to its unique biochemical structure. The protein possesses antioxidant properties such as binding copper tightly and iron weakly, scavenging free radicals, e.g., hypochlorous acid (HOCl) and Peroxynitrite (ONOOH) and providing thiol group (-SH). Whether it is chronic or acute, during many pathological conditions, biomarkers of oxidative protein damage increase and this observation continues with considerable oxidation of human serum albumin. There is an important necessity to specify its interactions with Reactive Oxygen Species. Generally, it may lower the availability of pro-oxidants and be preferentially oxidized to protect other macromolecules but all these findings make it necessary that researchers give a more detailed explanation of albumin and its relations with oxidative stress.
Clinical laboratory 11/2013; 59(9-10):945-52. DOI:10.7754/Clin.Lab.2012.121115 · 1.13 Impact Factor
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The purpose of the present study was to retrospectively analyse the impact of human albumin (HA) substitution on organ function in patients undergoing orthotopic liver transplantation (OLT).Methods
We retrospectively analysed chart data of 15 hypoalbuminaemic patients who received continuous infusion of HA (100 g∙d−1) for 7 days following OLT and matched them with 15 control patients for severity scores at admission. Primary endpoint was a difference in mean “Sequential Organ Failure Assessment” (SOFA) score during 14 days following OLT. Secondary endpoints included SOFA subscores, length of intensive care unit (ICU) stay, ICU mortality, 1-year mortality, fluid balance, colloid osmotic pressure (COP), serum albumin and total protein concentrations.ResultsSubstitution of HA was associated with a lower mean SOFA score as compared to control (11.0 ± 3.6 vs. 13.4 ± 3.7; P < 0.001). Patients treated with HA also exhibited lower cardiovascular SOFA subscore and higher COP, serum albumin and total protein concentrations. There were no significant differences in fluid balance, length of ICU stay, ICU mortality, or 1-year mortality.Conclusions
The present data suggest that continuous infusion of HA may preserve cumulative organ function (as measured by SOFA score) with emphasis on cardiovascular function in patients following OLT.This article is protected by copyright. All rights reserved.
Clinical Transplantation 11/2014; 29(1). DOI:10.1111/ctr.12486 · 1.52 Impact Factor
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