Dextran sulfate modulates MAP kinase signaling and reduces endothelial injury in a rat aortic clamping model Yara Banz, MD, PhD, Thusitha Gajanayake,

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Dextran sulfate modulates MAP kinase signaling and reduces endothelial injury in a rat aortic clamping model Yara Banz, MD, PhD, Thusitha Gajanayake, PhD, Katja Matozan, Zhihong Yang, PhD, Robert Rieben, PhD Journal of Vascular Surgery Volume 50, Issue 1, Pages 161-170 (July 2009) DOI: 10.1016/j.jvs.2009.01.067 Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 1 Summary of the experimental design. DXS, dextran sulfate; DXS-Fluo, fluorescein-labeled DXS; NaCl, saline controls; Hep III, heparinase III; Hep III buffer, heparinase III buffer only; n, number of animals per group. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 2 Immunofluorescence staining for complement C1q, C4b/c, C3b/c, and C9 on rat aortic tissue. Essentially no or minimal complement staining following ischemia-only (I-only). Complement activation and deposition after 90 minutes ischemia /120 minutes reperfusion following NaCl administration as well as after infusion of heparinase (Hep III)/120 minutes reperfusion. Dextran sulfate (DXS) clearly reduces complement deposition. Scale bar represents 100µm. All images are representative of at least 4 scored sections per experiment. Grading (average score ± standard deviation); where 0: no staining, 1: minimal focal or diffuse staining, 2: moderately strong focal or diffuse staining, 3: extensive focal or diffuse staining. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 3 Quantification of fluorescence intensity for complement staining/deposition of C1q, C4b/c, C3b/c, and C9. Histograms show a representative image of staining intensity (fluorescence, x-axis) from one of at least 4 individual experiments. Shift of the curve towards the right indicates increased intensity and thus increased complement deposition. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 4 Von Willebrand (vWF) and heparan sulfate proteoglycan (HSPG) staining on rat aorta. Circumferential positive staining for vWF in all experimental settings. Circumferential surface and wall HSPG staining in ischemia-only (I-only) controls and DXS-treated aorta. Diminished/abrogated HSPG staining in NaCl controls and heparinase-treated aortas. Scale bar represents 100µm. All images are representative of at least 4 scored sections per experiment. Grading (average score ± standard deviation); where 0: no staining, 1: minimal focal or diffuse staining, 2: moderately strong focal or diffuse staining, 3: extensive focal or diffuse staining. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 5 A, Immunofluorescence staining for tissue factor. Yellow arrowheads highlight surface tissue factor expression. Marked increase in tissue factor expression in the NaCl group as compared to aortas from DXS-treated animals and ischemia-only controls (I-only). Native (normal) aortas are used as a control. All images are representative of at least 4 scored sections per experiment. B, Image J software quantification of fluorescence intensity and grading of staining. Left: the histogram shows a representative image of staining intensity (fluorescence, x-axis) from one of at least 4 individual experiments. Shift of the curve towards the right indicates increased intensity and thus increased tissue factor expression. Right: grading (average score ± standard deviation); where 0: no staining, 1: minimal focal or diffuse staining, 2: moderately strong focal or diffuse staining, 3: extensive focal or diffuse staining. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 6 A, Localized binding of fluorescein-labeled DXS (DXS-Fluo) to ischemically damaged aorta as well as heparinase-treated aorta. Yellow arrows show DXS binding. Additional binding deeper within the aortic wall (particularly following heparinase treatment) is not marked with yellow arrows to retain clarity. No binding found to non-ischemic aorta. Scale bar represents 50 µm. B, Representative images of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining on aorta from normal, DXS, and NaCl animals. Positive nuclei stain brown (see black arrow and inlay), indicating apoptosis. Scale bar represents 50 µm. Columns represent mean ± standard deviation of percent TUNEL positive nuclei per high power field, P = 0.032 for DXS vs. NaCl and P = 0.047 for normal vs. NaCl. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 7 A, Western Blot results for MAPK activation. Ratio of phosphorylated (activated) p38 MAPK to p38 MAPK in aortic tissue samples from normal, ischemia-only (I-only), NaCl controls and DXS-treated animals. Significant increase in the NaCl group as compared to normal aorta (P = 0.02). DXS treatment and ischemia-only did not affect p38 MAPK activation (P = 0.110, P = 0.440 respectively). Ratio of phosphorylated (activated) c-Jun NH2-terminal kinase (JNK) to JNK in aortic tissue samples (B). Significant increase in all groups as compared to normal aorta (P < 0.005). DXS treatment significantly reduced JNK activation versus NaCl controls (P = 0.043). C, Ratio of phosphorylated (activated) ERK1/2 to ERK1/2 in aortic tissue samples. Significant increase in all groups as compared to normal aorta (P < 0.005). DXS treatment significantly reduced ERK1/2 activation versus NaCl controls (P = 0.005). All data are mean ± standard deviation. B and C, Representative images from immuno-histochemical staining for JNK and ERK1/2 reveal reduced staining in native/normal and DXS aortas as compared to control NaCl aortas (brown color). D, Image of representative Western Blot for native and phosphorylated p38 MAPK, ERK1/2 and JNK. Loading of 40 µg per well, individual lanes represent one single experiment. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions

Fig 8 Representative images from immuno-histochemical staining for nuclear factor (NF) kappa B reveal reduced nuclear staining in native/normal and DXS aortas as compared to NaCl control aortas. Nuclear positivity appears as a brown staining (see arrow heads in inlay). Scale bar represents 50µm. Quantification of staining intensity using Image J software. The graph represents the total area of positivity (brown nuclei) for NF kappa B staining on aortic samples. Bars represent mean ± standard deviation. Journal of Vascular Surgery 2009 50, 161-170DOI: (10.1016/j.jvs.2009.01.067) Copyright © 2009 Society for Vascular Surgery Terms and Conditions