Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair

Korf-Klingebiel M, Reboll MR, Grote K, Schleiner H, Wang Y, Wu X, Klede S, Mikhed Y, Bauersachs J, Klintschar M, Rudat C, et al. (2019)
Circulation research.

Zeitschriftenaufsatz | E-Veröff. vor dem Druck | Englisch
 
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Abstract / Bemerkung
RATIONALE: Mechanistic insight into the inflammatory response after acute myocardial infarction (MI) may inform new molecularly-targeted treatment strategies to prevent chronic heart failure.; OBJECTIVE: We identified the sulfatase SULF2 in an in silico secretome analysis in bone marrow cells from patients with acute MI and detected increased sulfatase activity in myocardial autopsy samples. SULF2 (Sulf2 in mice) and its isoform SULF1 (Sulf1) act as endo-sulfatases removing 6 O sulfate groups from heparan sulfate (HS) in the extracellular space, thus eliminating docking sites for HS binding proteins. We hypothesized that the Sulfs have a role in tissue repair after MI.; METHODS AND RESULTS: Both Sulfs were dynamically upregulated after coronary artery ligation in mice, attaining peak expression and activity levels during the first week after injury. Sulf2 was expressed by monocytes and macrophages, Sulf1 by endothelial cells and fibroblasts. Infarct border-zone capillarization was impaired, scar size increased, and cardiac dysfunction more pronounced in mice with a genetic deletion of either Sulf1 or Sulf2. Studies in bone marrow-chimeric Sulf-deficient mice and Sulf-deficient cardiac endothelial cells established that inflammatory cell-derived Sulf2 and endothelial cell-autonomous Sulf1 promote angiogenesis. Mechanistically, both Sulfs reduced HS sulfation in the infarcted myocardium, thereby diminishing vascular endothelial growth factor A (Vegfa) interaction with HS. Along this line, both Sulfs rendered infarcted mouse heart explants responsive to the angiogenic effects of HS-binding Vegfa164 but did not modulate the angiogenic effects of non-HS-binding Vegfa120. Treating wild-type mice systemically with the small molecule HS antagonist surfen (bis 2 methyl-4-amino-quinolyl-6-carbamide, 1 mg/kg/day) for 7 days after MI released Vegfa from HS, enhanced infarct border-zone capillarization, and exerted sustained beneficial effects on cardiac function and survival.; CONCLUSIONS: These findings establish HS-editing Sulfs as critical inducers of postinfarction angiogenesis and identify HS sulfation as a therapeutic target for ischemic tissue repair.
Erscheinungsjahr
2019
Zeitschriftentitel
Circulation research
eISSN
1524-4571
Page URI
https://pub.uni-bielefeld.de/record/2937243

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Korf-Klingebiel M, Reboll MR, Grote K, et al. Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair. Circulation research. 2019.
Korf-Klingebiel, M., Reboll, M. R., Grote, K., Schleiner, H., Wang, Y., Wu, X., Klede, S., et al. (2019). Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair. Circulation research. doi:10.1161/CIRCRESAHA.119.315023
Korf-Klingebiel, M., Reboll, M. R., Grote, K., Schleiner, H., Wang, Y., Wu, X., Klede, S., Mikhed, Y., Bauersachs, J., Klintschar, M., et al. (2019). Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair. Circulation research.
Korf-Klingebiel, M., et al., 2019. Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair. Circulation research.
M. Korf-Klingebiel, et al., “Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair”, Circulation research, 2019.
Korf-Klingebiel, M., Reboll, M.R., Grote, K., Schleiner, H., Wang, Y., Wu, X., Klede, S., Mikhed, Y., Bauersachs, J., Klintschar, M., Rudat, C., Kispert, A., Niessen, H.W., Lübke, T., Dierks, T., Wollert, K.C.: Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair. Circulation research. (2019).
Korf-Klingebiel, Mortimer, Reboll, Marc R, Grote, Karsten, Schleiner, Hauke, Wang, Yong, Wu, Xuekun, Klede, Stefanie, Mikhed, Yuliya, Bauersachs, Johann, Klintschar, Michael, Rudat, Carsten, Kispert, Andreas, Niessen, Hans Wm, Lübke, Torben, Dierks, Thomas, and Wollert, Kai C. “Heparan Sulfate-Editing Extracellular Sulfatases Enhance Vascular Endothelial Growth Factor Bioavailability for Ischemic Heart Repair”. Circulation research (2019).

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