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1. Incorporation of heparin-binding proteins into preformed dextran sulfate-chitosan nanoparticles

Author

Zaman P, Wang J, Blau A, Wang W, Li T, Kohane DS, Loscalzo J, and Zhang YY

Subjects
polyelectrolyte complex, polysaccharide, glycan, glycosaminoglycan, Medicine (General), R5-920
Abstract

Paula Zaman,1 Julia Wang,1 Adam Blau,1 Weiping Wang,2 Tina Li,1 Daniel S Kohane,2 Joseph Loscalzo,1 Ying-Yi Zhang1 1Department of Medicine, Brigham and Women’s Hospital, 2Department of Anesthesiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Abstract: Incorporation of proteins into dextran sulfate (DS)-chitosan (CS) nanoparticles (DSCS NPs) is commonly performed using entrapment procedures, in which protein molecules are mixed with DS and CS until particle formation occurs. As DS is an analog of heparin, the authors examined whether proteins could be directly incorporated into preformed DSCS NPs through a heparin binding domain-mediated interaction. The authors formulated negatively-charged DSCS NPs, and quantified the amount of charged DS in the outer shell of the particles. The authors then mixed the DSCS NPs with heparin-binding proteins (SDF-1α, VEGF, FGF-2, BMP-2, or lysozyme) to achieve incorporation. Data show that for DSCS NPs containing 100 nmol charged glucose sulfate units in DS, up to ~1.5 nmol of monomeric or ~0.75 nmol of dimeric heparin-binding proteins were incorporated without significantly altering the size or zeta potential of the particles. Incorporation efficiencies of these proteins were 95%–100%. In contrast, serum albumin or serum globulin showed minimal incorporation (8% and 4%, respectively) in 50% physiological saline, despite their large adsorption in water (80% and 92%, respectively). The NP-incorporated SDF-1α and VEGF exhibited full activity and sustained thermal stability. An in vivo aerosolization study showed that NP-incorporated SDF-1α persisted in rat lungs for 72 h (~34% remaining), while free SDF-1α was no longer detectable after 16 h. As many growth factors and cytokines contain heparin-binding sites/domains, incorporation into preformed DSCS NPs could facilitate in vivo applications of these proteins. Keywords: polyelectrolyte complex, polysaccharide, glycan, glycosaminoglycan

Published
2016

6. Circulating CD4+T/methylation signatures of network-oriented SOCS3, ITGAL, NFIC, NCOR2, PGK1 genes associate with hemodynamics in pulmonary arterial hypertension patients

Author

Benincasa, G, primary, Maron, B A, additional, Affinito, O, additional, D'Alto, M, additional, Franzese, M, additional, Argiento, P, additional, Schiano, C, additional, Romeo, E, additional, Bontempo, P, additional, Golino, P, additional, Berrino, L, additional, Loscalzo, J, additional, and Napoli, C, additional

Published
2021
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9. NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review

Author

Oldham, WM, Hemnes, AR, Aldred, MA, Barnard, J, Brittain, EL, Chan, SY, Cheng, F, Cho, MH, Desai, AA, Garcia, JGN, Geraci, MW, Ghiassian, SD, Hall, KT, Horn, EM, Jain, M, Kelly, RS, Leopold, JA, Lindstrom, S, Modena, BD, Nichols, WC, Rhodes, CJ, Sun, W, Sweatt, AJ, Vanderpool, RR, Wilkins, MR, Wilmot, B, Zamanian, RT, Fessel, JP, Aggarwal, NR, Loscalzo, J, Xiao, L, British Heart Foundation, and The Academy of Medical Sciences

Subjects
Lung Diseases, Research Report, Pulmonary Circulation, Biomedical Research, drug repurposing, integrative omics, precision medicine, master clinical trial protocol, Computational Biology, systems biology, United States, Article, 1117 Public Health and Health Services, Education, Review Literature as Topic, Cardiovascular System & Hematology, Cardiovascular Diseases, pulmonary hypertension, Humans, Vascular Diseases, National Heart, Lung, and Blood Institute (U.S.), 1102 Cardiorespiratory Medicine and Haematology
Abstract

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.

Published
2020

15. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Author

Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, Zheng, A, Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, and Zheng, A

Abstract

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

Published
2019

21. Vitamin and Trace Mineral Deficiency and Excess (Chapter 326)

Author

Jameson, J. Larry, Fauci, Anthony S., Kasper, Dennis L., Hauser, Stephen L., Longo, Dan L., Loscalzo, Joseph, Jameson, J L ( J. Larry ), Fauci, A S ( Anthony S. ), Kasper, D L ( Dennis L. ), Hauser, S L ( Stephen L. ), Longo, D L ( Dan L. ), Loscalzo, J ( Joseph ), Suter, Paolo M, Russell, R M, Jameson, J. Larry, Fauci, Anthony S., Kasper, Dennis L., Hauser, Stephen L., Longo, Dan L., Loscalzo, Joseph, Jameson, J L ( J. Larry ), Fauci, A S ( Anthony S. ), Kasper, D L ( Dennis L. ), Hauser, S L ( Stephen L. ), Longo, D L ( Dan L. ), Loscalzo, J ( Joseph ), Suter, Paolo M, and Russell, R M

Published
2018

24. Vitamin and trace Mineral Deficiency and Excess

Author

Kasper, D, Fauci, A, Hauser, S, Longo, D, Jameson, J L, Loscalzo, J, Kasper, D ( D ), Fauci, A ( A ), Hauser, S ( S ), Longo, D ( D ), Jameson, J L ( J L ), Loscalzo, J ( J ), Suter, P M, Kasper, D, Fauci, A, Hauser, S, Longo, D, Jameson, J L, Loscalzo, J, Kasper, D ( D ), Fauci, A ( A ), Hauser, S ( S ), Longo, D ( D ), Jameson, J L ( J L ), Loscalzo, J ( J ), and Suter, P M

Published
2015

27. Vitamin and Trace Mineral Deficiency and Excess (2012) - Chapter 74

Author

Longo, D L, Fauci, A S, Kaspar, D L, Hauser, S L, Jameson, J L, Loscalzo, J, Longo, D L ( D L ), Fauci, A S ( A S ), Kaspar, D L ( D L ), Hauser, S L ( S L ), Jameson, J L ( J L ), Loscalzo, J ( J ), Russell, R M, Suter, P M, Longo, D L, Fauci, A S, Kaspar, D L, Hauser, S L, Jameson, J L, Loscalzo, J, Longo, D L ( D L ), Fauci, A S ( A S ), Kaspar, D L ( D L ), Hauser, S L ( S L ), Jameson, J L ( J L ), Loscalzo, J ( J ), Russell, R M, and Suter, P M

Published
2012

29. Vitamin and trace mineral deficiencies and excess

Author

Longo, D L, Fauci, A S, Kasper, D L, Hauser, S L, Jameson, J L, Loscalzo, J, Longo, D L ( D L ), Fauci, A S ( A S ), Kasper, D L ( D L ), Hauser, S L ( S L ), Jameson, J L ( J L ), Loscalzo, J ( J ), Russel, R M, Suter, P M, Longo, D L, Fauci, A S, Kasper, D L, Hauser, S L, Jameson, J L, Loscalzo, J, Longo, D L ( D L ), Fauci, A S ( A S ), Kasper, D L ( D L ), Hauser, S L ( S L ), Jameson, J L ( J L ), Loscalzo, J ( J ), Russel, R M, and Suter, P M

Published
2011

30. Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction

Author

GALASSO, GENNARO, Schiekofer S, Sato K, Shibata R, Handy DE, Ouchi N, Leopold JA, Loscalzo J, Walsh K., Galasso, Gennaro, Schiekofer, S, Sato, K, Shibata, R, Handy, De, Ouchi, N, Leopold, Ja, Loscalzo, J, and Walsh, K.

Abstract

Several vascular disease are characterized by elevated levels of reactive oxygen species (ROS). Vascular endothelium is protected from oxidant stress by expressing enzymes such as glutathione peroxidase type 1 (GPx-1). In this study, we investigated the effect of vascular oxidant stress on ischemia-induced neovascularization in a murine model of homozygous deficiency of GPx-1. GPx-1-deficient mice showed impaired revascularization following hindlimb ischemic surgery based on laser Doppler measurements of blood flow and capillary density in adductor muscle. GPx-1-deficient mice also showed an impaired ability to increase endothelial progenitor cell (EPC) levels in response to ischemic injury or subcutaneous administration of vascular endothelial growth factor protein. EPCs isolated from GPx-1-deficient mice showed a reduced ability to neutralize oxidative stress in vitro, which was associated with impaired migration toward vascular endothelial growth factor and increased sensitivity to ROS-induced apoptosis. EPCs isolated from GPx-1-deficient mice were impaired in their ability to promote angiogenesis in wild-type mice, whereas wild-type EPCs were effective in stimulating angiogenesis in GPx-1-deficient mice. These data suggest that EPC dysfunction is a mechanism by which elevated levels of ROS can contribute to vascular disease

Published
2006

33. New approaches to antiplatelet therapy

Author

Loscalzo J and Ezratty Am

Subjects
Secondary prevention, Platelet Aggregation, business.industry, Fibrinogen receptor, Prostanoid, Hematology, General Medicine, Platelet Activation, Bioinformatics, chemistry.chemical_compound, chemistry, Cardiovascular Diseases, Humans, Medicine, Platelet, cardiovascular diseases, Relative potency, business, Platelet Aggregation Inhibitors, 5-HT receptor, Discovery and development of direct thrombin inhibitors
Abstract

The importance of platelets in the pathophysiology of cardiovascular and cerebrovascular disorders has been demonstrated by numerous clinical and pathological studies. Conventional antiplatelet agents are effective in both the primary and secondary prevention of vascular disorders, but suffer for the combined shortcomings of lack of selectivity and relative potency. Many new antiplatelet agents have been developed to overcome these differences, including serotonin receptor antagonists, prostanoid derivatives and antagonists, fibrinogen receptor antagonists, and selective thrombin inhibitors. In this review we consider the mechanisms by which these novel antiplatelet agents impair platelet function and their potential clinical utility.

Published
1991

37. Analysis of a nucleotide-binding site of 5-lipoxygenase by affinity labelling: binding characteristics and amino acid sequences

Author

Zhang, Y Y, Hammarberg, T, Radmark, O, Samuelsson, B, Ng, C F, Funk, C D, and Loscalzo, J

Subjects
Kinetics, Adenosine Triphosphate, Arachidonate 5-Lipoxygenase, Binding Sites, Sequence Homology, Amino Acid, Molecular Sequence Data, Humans, Affinity Labels, Electrophoresis, Polyacrylamide Gel, Amino Acid Sequence, Chromatography, High Pressure Liquid, Recombinant Proteins, Research Article
Abstract

5-Lipoxygenase (5LO) catalyses the first two steps in the biosynthesis of leukotrienes, which are inflammatory mediators derived from arachidonic acid. 5LO activity is stimulated by ATP; however, a consensus ATP-binding site or nucleotide-binding site has not been found in its protein sequence. In the present study, affinity and photoaffinity labelling of 5LO with 5'-p-fluorosulphonylbenzoyladenosine (FSBA) and 2-azido-ATP showed that 5LO bound to the ATP analogues quantitatively and specifically and that the incorporation of either analogue inhibited ATP stimulation of 5LO activity. The stoichiometry of the labelling was 1.4 mol of FSBA/mol of 5LO (of which ATP competed with 1 mol/mol) or 0.94 mol of 2-azido-ATP/mol of 5LO (of which ATP competed with 0.77 mol/mol). Labelling with FSBA prevented further labelling with 2-azido-ATP, indicating that the same binding site was occupied by both analogues. Other nucleotides (ADP, AMP, GTP, CTP and UTP) also competed with 2-azido-ATP labelling, suggesting that the site was a general nucleotide-binding site rather than a strict ATP-binding site. Ca(2+), which also stimulates 5LO activity, had no effect on the labelling of the nucleotide-binding site. Digestion with trypsin and peptide sequencing showed that two fragments of 5LO were labelled by 2-azido-ATP. These fragments correspond to residues 73-83 (KYWLNDDWYLK, in single-letter amino acid code) and 193-209 (FMHMFQSSWNDFADFEK) in the 5LO sequence. Trp-75 and Trp-201 in these peptides were modified by the labelling, suggesting that they were immediately adjacent to the C-2 position of the adenine ring of ATP. Given the stoichiometry of the labelling, the two peptide sequences of 5LO were probably near each other in the enzyme's tertiary structure, composing or surrounding the ATP-binding site of 5LO.

Published
2000

40. Aspirin.

Author

Awtry EH, Loscalzo J, Awtry, E H, and Loscalzo, J

Published
2000

41. Endothelial injury, vasoconstriction, and its prevention

Author

Loscalzo, J

Subjects
S-Nitrosothiols, Arteriosclerosis, Vasoconstriction, cardiovascular system, Animals, Humans, Endothelium, Vascular, Nitric Oxide, Muscle, Smooth, Vascular, Research Article, Mercaptoethanol, Nitroso Compounds
Abstract

The endothelial cell is an important determinant of vascular tone, and performs this function by the elaboration of several factors that modulate the contractile state of the vascular smooth muscle cell. In response to physical and molecular factors in the vasculature, the endothelial cell maintains basal vascular tone by the elaboration of prostacyclin, endothelium-derived relaxing factor, and endothelium-derived hyperpolarizing factor, all of which reduce vascular smooth muscle tone. With progressive dysfunction of or injury to the endothelium, however, vascular smooth muscle tone increases in response to reduced production or availability of these endothelium-derived vasorelaxants and increased production of the vasoconstrictor substances, endothelin and endothelium-derived constricting factor(s). Common determinants of endothelial dysfunction that contribute substantially to the progress of vascular diseases include hypercholesterolemia, hypertension, tobacco use, and diabetes mellitus. Current approaches to the reversal or attenuation of the progression of vascular diseases in which the endothelium plays an important role focus on pharmacotherapeutic methods by which to restore normal endothelial function.

Published
1995

50. O-Raffinose Crosslinking Substantially Ameliorates the Vasoconstrictive and Nitric-Oxide-Inactivating Effects of Unmodified Human Hemoglobin in the Rat

Author

NAVAL BLOOD RESEARCH LAB BOSTON MA, Lieberthal, W., Fuhro, R., Freedman, J. E., Toolan, G., Loscalzo, J., NAVAL BLOOD RESEARCH LAB BOSTON MA, Lieberthal, W., Fuhro, R., Freedman, J. E., Toolan, G., and Loscalzo, J.

Abstract

We studied the hemodynamic effects of a 20% exchange transfusion with whole blood or highly purified human hemoglobin Ao. We compared the effects of unmodified hemoglobin with o-raffinose crosslinked oligomers of hemoglobin (modified hemoglobin). The unmodified SFH increased systemic vascular resistance (SVR) by approx. 40%, and renal vascular resistance (RVR) by approx. 25%. Cardiac output was markedly reduced (by approx. 20%) and mean arterial pressure (MAP) only modestly increased (by approx. 13%). In contrast, the modified hemoglobin solution caused less increase in SVR (approx. 14%) and did not alter renal hemodynamics or blood pressure. We also compared the ability of the unmodified and crosslinked hemoglobins to inactivate nitric oxide (NO) in vitro using three separate assays; platelet NO release, NO-stimulated platelet cGMP production and EDRF-mediated inhibition of platelet aggregation. The unmodified hemoglobin inactivated NO to a markedly greater extent than the o-raffinose crosslinked hemoglobin in all three assays. Thus, chemical crosslinking with o-raffinose reduces the systemic and renal vasoconstriction as well as the NO-inactivating effects of hemoglobin. We suggest that the change in the vasoactive effects of unmodified hemoglobin induced by o-raffinose crosslinking is related to the associated reduction in NO-inactivation.

Published
1997

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