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HEPARANASE EXPRESSION AND ACTIVITY ARE INCREASED IN PLATELETS DURING CLINICAL SEPSIS
Author
Eustes, Alicia S.
Campbell, Robert A.
Middleton, Elizabeth A.
Tolley, Neal D.
Manne, Bhanu K.
Montenont, Emilie
Rowley, Jesse W.
Krauel, Krystin
Blair, Antoinette
Guo, Li
Kosaka, Yasuhiro
Medeiros-de-Moraes, Isabel M.
Lacerda, Marcus
Hottz, Eugenio D.
Faria Neto, Hugo Castro
Zimmerman, Guy A.
Weyrich, Andrew S.
Petrey, Aaron
Rondina, Matthew T.
Campbell, Robert A.
Middleton, Elizabeth A.
Tolley, Neal D.
Manne, Bhanu K.
Montenont, Emilie
Rowley, Jesse W.
Krauel, Krystin
Blair, Antoinette
Guo, Li
Kosaka, Yasuhiro
Medeiros-de-Moraes, Isabel M.
Lacerda, Marcus
Hottz, Eugenio D.
Faria Neto, Hugo Castro
Zimmerman, Guy A.
Weyrich, Andrew S.
Petrey, Aaron
Rondina, Matthew T.
Affilliation
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA / University of Iowa. Internal Medicine. Hospitals and Clinics Pathology. Iowa City, Iowa, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Freiburg. Heart Center. Department of Cardiology and Angiology I. Freiburg, Germany.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Federal University of Juiz de Fora. Department of Biochemistry. Immunothrombosis Laboratory. Juiz de Fora, MG, Brazil / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA / Department of Internal Medicine and GRECC. George E. Wahlen VAMC. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Freiburg. Heart Center. Department of Cardiology and Angiology I. Freiburg, Germany.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Federal University of Juiz de Fora. Department of Biochemistry. Immunothrombosis Laboratory. Juiz de Fora, MG, Brazil / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA.
University of Utah. Department of Internal Medicine and Molecular Medicine Program. Salt Lake City, Utah, USA / University of Utah. Department of Pathology. Salt Lake City, Utah, USA / Department of Internal Medicine and GRECC. George E. Wahlen VAMC. Salt Lake City, Utah, USA.
Abstract
Background: Heparanase (HPSE) is the only known mammalian enzyme that can degrade heparan sulfate. Heparan sulfate proteoglycans are essential components of the glycocalyx, and maintain physiological barriers between the blood and endothelial cells. HPSE increases during sepsis, which contributes to injurious glyocalyx degradation, loss of endothelial barrier function, and mortality. Objectives: As platelets are one of the most abundant cellular sources of HPSE, we sought to determine whether HPSE expression and activity increases in human platelets during clinical sepsis. We also examined associations between platelet HPSE expression and clinical outcomes. Patients/methods: Expression and activity of HPSE was determined in platelets isolated from septic patients (n = 59) and, for comparison, sex-matched healthy donors (n = 46) using complementary transcriptomic, proteomic, and functional enzymatic assays. Septic patients were followed for the primary outcome of mortality, and clinical data were captured prospectively for septic patients. Results: The mRNA expression of HPSE was significantly increased in platelets isolated from septic patients. Ribosomal footprint profiling, followed by [S35] methionine labeling assays, demonstrated that HPSE mRNA translation and HPSE protein synthesis were significantly upregulated in platelets during sepsis. While both the pro- and active forms of HPSE protein increased in platelets during sepsis, only the active form of HPSE protein significantly correlated with sepsis-associated mortality. Consistent with transcriptomic and proteomic upregulation, HPSE enzymatic activity was also increased in platelets during sepsis. Conclusions: During clinical sepsis HPSE, translation, and enzymatic activity are increased in platelets. Increased expression of the active form of HPSE protein is associated with sepsis-associated mortality.
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