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Joseph M. Rifkind, Ph.D., Senior Investigator Chief, Molecular Dynamics Section E-mail: rifkindj@grc.nia.nih.gov

Biography: Dr. Joseph M. Rifkind received his Ph.D. in Physical Chemistry from Columbia University in 1966. He obtained postdoctoral training in protein chemistry at the University of Minnesota and joined the Gerontology Research Center of what was then part of National Institute of Child Health and Human Development (NICHD) in1968. He is the chief of the Molecular Dynamics Section. He is a member of the American Chemical Society, the Biophysical Society, the American Association for the Advancement of Science, the Gerontological Society of America, the International EPR (ESR) Society, and the International Society on Oxygen Transport to Tissue.

The Molecular Dynamics Section (MDS) under the direction of Joseph Rifkind is studying the role of oxygen in biological systems and how it influences the aging process. The red cell is responsible for the transport of oxygen through the circulatory system and the delivery of oxygen to the tissues. In the red cell, oxygen is reversibly bound to Fe(II) of hemoglobin with molecular oxygen released at reduced oxygen pressure. However, both oxygen and iron can undergo oxidative and reductive processes with the Fe(II) oxidized to Fe(III) and Fe(IV), while oxygen can be reduced to superoxide, hydrogen peroxide and hydroxyl radicals. The ramifications of these oxidative reactions in red cells have been the focus of the Molecular Dynamics Section.

A multipronged approach to red cell oxidative stress has been employed directed at understanding the source of this oxidative stress and its physiological ramifications. (1) We have investigated the mechanism whereby oxyradicals are produced under hypoxic conditions. Using electron paramagnetic resonance combined with visible spectroscopy, fluorescence spectroscopy and molecular dynamics simulations, we are studying the hemoglobin autoxidation process which produces oxyradicals. (2) We have been studying how these processes produce cellular damage despite the presence of antioxidants and the enzyme systems designed to protect from oxidative stress. Under hypoxic conditions, there is an enhanced affinity of hemoglobin for the erythrocyte membrane. The superoxide that is liberated from hemoglobin bound to the membrane is relatively inaccessible to cytoplasmic superoxide dismutase and ideally located to damage the red cell membrane. This hypothesis is supported by the formation of protein cross-links and a decrease in red cell deformability when red cells are incubated under hypoxic conditions. An additional source for membrane damage is the accumulation of hydrophobic heme degradation products in the membrane. (3) Impaired red cell deformability found to be induced under hypoxia is also associated with subject aging. We are very interested in understanding altered deformability in the aged as well as other decrements in blood rheology. Our studies suggest a link with oxidative stress which could originate in hypoxic induced oxyradical production. Recent results indicate greater oxidation in venous blood than arterial blood confirming the production of oxyradicals as blood passes through the capillary bed at reduced oxygen pressures. The physiological ramifications of red cell oxidative stress are currently being investigated by probing physiological effects that result from injecting into an animal blood containing red cells unable to deal with oxidative stress.

We have recently expanded our studies of the detrimental red cell oxidative processes into two areas. (1) We have extended our understanding of the red cell oxidative processes and how hemoglobin�membrane interactions contribute to red cell oxidative processes by bypassing the cellular protective mechanisms. In the course of these studies, we have studied the secondary oxidative processes, which irreversibly damage the heme, and used the damaged high-spin rhombic heme and fluorescent degradation products as markers for the extent of red cell oxidative processes. (2) We have initiated a program directed at investigating the possibility that red cell interactions with amyloid fibrils may contribute to the toxicity of these fibrils and the pathophysiology of Alzheimer's disease.

At the same time, we have initiated a new program to investigate the relationship between hemoglobin oxidation and the role of the red cell in regulating nitric oxide delivery to the vasculature. This program has identified an important reaction between deoxygenated hemoglobin and nitrite that produces a labile reactive form of nitric oxide, which can improve the flow of blood through the microcirculation.

Publications:

Nagababu E, Rifkind JM. Measurement of plasma nitrite by chemiluminescence without interference of S-, N-nitroso and nitrated species. Free Radic Biol Med. 42(8): 1146-1154, 2007.

Rifkind JM, Nagababu E, Barbiro-Michaely E, Ramasamy S, Pluta RM, Mayevsky A. Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell NO. Nitric Oxide. 16(4): 448-456, 2007.

Lee GD, Longo DL, Wang Y, Rifkind JM, Abdul-Raman L, Mamczarz JA, Duffy KB, Spangler EL, Taub DD, Mattson MP, Ingram DK. Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Cancer Res. 12(1): 198-205, 2006.

Nagababu E, Ramasamy S, Rifkind JM. S-Nitrosohemoglobin: A mechanism for its formation in conjunction with nitrite reduction by deoxyhemoglobin. Nitric Oxide. 15(1): 20-29, 2006.

Rifkind JM, Nagababu E, Ramasamy S. Nitric oxide redox reactions and red cell biology. Antioxid Redox Signal. 8(7-8): 1193-1203, 2006.

Ravi LB, Poosala S, Ahn D, Chrest FJ, Spangler EL, Jayakumar R, Nagababu E, Mohanty JG, Talan M, Ingram DK, Rifkind JM. Red cell interactions with amyloid-beta(1-40) fibrils in a murine model. Neurobiol Dis. 19(1-2): 28-37, 2005.

Venkatesh B, Venkatesh S, Jayadevan S, Rifkind JM, Manoharan PT. Studies on heme release from normal and metal ion reconstituted hemoglobin mediated through ionic surfactant. Biopolymers. 80(1): 18-25, 2005.

Nagababu E, Rifkind JM. Heme degradation by reactive oxygen species. Antioxid Redox Signal. 6(6): 967-978, 2004.

Jia Y, Ramasamy S, Wood F, Alayash AI, Rifkind JM. Cross-linking with O-raffinose lowers oxygen affinity and stabilizes haemoglobin in a non-cooperative T-state conformation. Biochem J. 384(Pt 2): 367-375, 2004.

Ravi LB, Mohanty JG, Chrest FJ, Jayakumar R, Nagababu E, Usatyuk PV, Natarajan V, Rifkind JM. Influence of b-amyloid fibrils on the interactions between red blood cells and endothelial cells. Neurol Res. 26(5): 579-585, 2004.

Rifkind JM, Ramasamy S, Manoharan PT, Nagababu E, Mohanty JG. Redox reactions of hemoglobin. Antioxid Redox Signal. 6(3): 657-666, 2004.

Rifkind JM, Nagababu E, Ramasamy S, Ravi LB. Hemoglobin redox reactions and oxidative stress. Redox Rep. 8(5): 234-237, 2003.

Nagababu E, Ramasamy S, Abernethy DR, Rifkind JM. Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J Biol Chem. 278(47): 46349-46356, 2003.

Jayakumar R, Kusiak JW, Chrest FJ, Demehin AA, Murali J, Wersto RP, Nagababu E, Ravi L, Rifkind JM. Red cell perturbations by amyloid b-protein. Biochim Biophys Acta. 1622(1): 20-28, 2003.

Murali J, Koteeswari D, Rifkind JM, Jayakumar R. Amyloid insulin interaction with erythrocytes. Biochem Cell Biol. 81(1): 51-59, 2003.

Ajmani RS, Fleg JL, Demehin AA, Wright JG, O'Connor F, Heim JM, Tarien E, Rifkind JM. Oxidative stress and hemorheological changes induced by acute treadmill exercise. Clin Hemorheol Microcirc. 28(1): 29-40, 2003.

Nagababu E, Chrest FJ, Rifkind JM. Hydrogen-peroxide-induced heme degradation in red blood cells: the protective roles of catalase and glutathione peroxidase. Biochim Biophys Acta. 1620(1-3): 211-217, 2003.

Demehin AA, Abugo OO, Jayakumar R, Lakowicz JR, Rifkind JM. Binding of hemoglobin to red cell membranes with eosin-5-maleimide-labeled band 3: analysis of centrifugation and fluorescence data. Biochemistry. 41(27): 8630-8637, 2002.

Nagababu E, Ramasamy S, Rifkind JM, Jia Y, Alayash AI. Site-specific cross-linking of human and bovine hemoglobins differentially alters oxygen binding and redox side reactions producing rhombic heme and heme degradation. Biochemistry. 41(23): 7407-7415, 2002.

Demehin AA, Abugo OO, Rifkind JM. The reduction of nitroblue tetrazolium by red blood cells: a measure of red cell membrane antioxidant capacity and hemoglobin-membrane binding sites. Free Radic Res. 34(6): 605-620, 2001.

Abugo OO, Balagopalakrishna C, Rifkind JM, Rudolph AS, Hess JR, Macdonald VW. Direct measurements of hemoglobin interactions with liposomes using EPR spectroscopy. Artif Cells Blood Substit Immobil Biotechnol. 29(1): 5-18, 2001.

Nagababu E, Chrest FJ, Rifkind JM. The origin of red cell fluorescence caused by hydrogen peroxide treatment. Free Radic Biol Med. 29(7): 659-663, 2000.

Nagababu E, Rifkind JM. Reaction of hydrogen peroxide with ferrylhemoglobin: superoxide production and heme degradation. Biochemistry. 39(40): 12503-12511, 2000.

Nagababu E, Rifkind JM. Heme degradation during autoxidation of oxyhemoglobin. Biochem Biophys Res Commun. 273(3): 839-845, 2000.

Ajmani RS, Metter EJ, Jaykumar R, Ingram DK, Spangler EL, Abugo OO, Rifkind JM. Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function. Neurobiol Aging. 21(2): 257-269, 2000.

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Updated: Thursday October 11, 2007