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Vascular Medicine Institute
University of Pittsburgh
BST E1240
200 Lothrop Street
Pittsburgh, PA 15261
Phone: 412-383-5853
Fax: 412-648-5980

N. Harold Raat, PhD

 

harold raat

 

Harold Raat, PhD

Adjunct Assistant Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine

Department of Anesthesiology
Erasmus Medical Center
Dr. Molewaterplein 40
3015 GD  Rotterdam
The Netherlands

Tel: +31-10 -704-3310
Fax: + 31-10-463-3722
e-mail: n.raat@erasmusmc.nl


   

Bio

Dr. Raat received his MSc. in Medical Biology from the University of Amsterdam. His PhD was obtained from the Department of Cell Physiology of the University of Nijmegen under the mentorship of Carel van Os and Rene Bindels, studying the role of signal transduction pathways in cell volume regulation. As a post doc he joined the department of Pharmacology of the Cardiovascular Research Institute Maastricht (CARIM) where, under the guidance of Dr. Jo de Mey, he studied the influence of local neuronal noradrenaline release on calcium sensitization in mesenteric arteries.

At the Department of Cardiology at St. Thomas' Hospital / King's College (Prof. M. Marber) in London he investigated the involvement of protein kinase C epsilon in ischemic precondition in Langendorf perfused mouse hearts.  He studied in a rat model of hemodilution the effects of storage of blood on its tissue oxygenation properties at the Department of Experimental Anesthesiology and Clinical Physiology (Prof C. Ince) of the Academic Medical Centre in Amsterdam.  He also evaluated the tissue oxygenation properties of the recombinant Hemoglobin based oxygen carrier rHb2.0 in a rat hemorraghic shock model.  As senior Research Fellow at the Pulmonary and Vascular Medicine Branch at the NHLBI at NIH he studied the protective effects of dietary nitrite on liver ischemia reperfusion injury and nitrite influx pathways in the red blood cell. Dr Raat is currently working at Erasmus University in The Netherlands.

Research Interests

Dietary nitrite effect on ischemia reperfusion injury and gene expression
Duranski et al. (Duranski et al. JCI 115: 1232, 2005) showed that only nanomolar amounts of nitrite are able to protect tissue from ischemia-reperfusion injury. These levels are close to the nitrite amounts that can be obtained via the diet and we wondered whether diet may modulate ischemia reperfusion (IR) injury. We showed in a mouse liver IR model that depletion of nitrite from the diet increased IR injury, while repletion of nitrite decreased IR injury.

The effect of nitrite depletion and supplementation on gene activation were demonstrated by DNA micro arrays and showed that under normoxic conditions there was a small effect of nitrite on gene expression that could only be detected using a sensitive analysis method. We also emphasized the importance of using the low nitrite supplemented with nitrite as a control instead of the normal diet. The effect of switching diet was much larger than the effect of nitrite under normoxic conditions. The effect of nitrite on gene expression during ischemia-reperfusion was much more pronounced and showed modulation of 36 genes that could be picked up by standard analysis methods. These findings suggest that it is important for researchers studying ischemia-reperfusion injury to measure dietary nitrite levels to minimize experimental variation.

body nitrate/nitrite cycle

Nitrite uptake mechanism in red blood cells
During hypoxia deoxyhemoglobin in the red blood cell will convert nitrite into NO that is able to escape the cell despite scavenging by hemoglobin and cause vessel relaxation (Cosby, Nature  Med. 12: 1498, 2003). Also deoxymyoglobin in muscle cells can convert nitrite into NO that plays a role in mitochondrial oxygen consumption (Shiva, Circ. Res. 100: 654, 2007). Recently nitrite also was found to be converted by mitochondrial cytochrome C into NO (Basu et al. JBC: Sep 28, 2008). It is therefore likely that intracellular and mitochondrial nitrite concentrations are tightly regulated to maintain NO levels within certain limits.  We are studying possible nitrite influx and efflux mechanisms that may be involved in the regulation of intracellular and mitochondrial nitrite concentrations.

nitrite influx

Reduction of the vasoconstrictive properties of the Hemoglobin based oxygen carrier (HBOC-201)
Hemoglobin based oxygen carriers (HBOC) are promising substitutes for blood transfusion especially to treat victims with severe blood loss outside the hospital. HBOC do not require crossmatching and can be stored at room temperature for several years. Hemoglobin-based oxygen carrier-201 (HBOC-201) is a bovine–hemoglobin-based blood substitute that is approved in South Africa for clinical use. Its clinical use in the US is not approved by the FDA mainly because of its vasoconstrictive properties.

In collaboration with Dr. Dan Freilich from the Naval Medical Research Center, we are currently investigating in a pig hemorrhagic shock model whether the simultaneous administration of nitrite with HBOC-201 can minimize its vasconstrictive effects.  A rat hemorrhagic shock model will be used to investigate further the kinetics of the reaction of nitrite with hemoglobin, the formation and stability of intermediate reaction products as well as other parameters altering the nitrite-hemoglobin interaction.


Key Publications

Raat NJ, Verhoeven AJ, Mik EG, Gouwerok CW, Verhaar R, Goedhart PT, de Korte D, Ince C. The effect of storage time of human red cells on intestinal microcirculatory oxygenation in a rat isovolemic exchange model. Crit Care Med. 2005;33(1):39-45.

Raat NJ, Liu JF, Doyle MP, Burhop KE, Klein J, Ince C. Effects of recombinant-hemoglobin solutions rHb2.0 and rHb1.1 on blood pressure, intestinal blood flow, and gut oxygenation in a rat model of hemorrhagic shock. J.Lab Clin.Med. 2005;145(1):21-32.            

Raat NJH, Berends F, Verhoeven AJ, de Korte D, Ince C. The age of stored red blood cell concentrates at the time of transfusion. Transfus Med. 2005;15(5):419-423. 

Gladwin MT, Raat NJH, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, Patel RP. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. AJP - Heart and Circulatory Physiology. 2006;291(5):H2026-H2035.  

Dezfulian C, Raat N, Shiva S, Gladwin MT. Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc.Res. 2007;75(2):327-338.        

Raat NJ, Ince C. Oxygenating the microcirculation: the perspective from blood transfusion and blood storage. Vox Sang. 2007;93(1):12-18.

Pubmed link