Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model Jianping Dai, MD, PhD, Liliane.

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Presentation transcript:

Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model Jianping Dai, MD, PhD, Liliane Louedec, BSc, Monique Philippe, BSc, Jean-Baptiste Michel, MD, PhD, Xavier Houard, PhD Journal of Vascular Surgery Volume 49, Issue 3, Pages 719-727 (March 2009) DOI: 10.1016/j.jvs.2008.09.057 Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 1 Reversible inhibition of platelet aggregation by AZD6140. A, Adenosine diphosphate (ADP; 5 μM) induced aggregation >50% of platelets in control plasma. B, In AZD6140-treated rats, ADP-induced platelet aggregation was potently inhibited at 2 hours after AZD6140 administration. C, Inhibition remained pronounced at 10 hours after treatment. D, Significant aggregation was observed after 24 hours. Diagrams A-D are representative of analysis performed on two rats. These data justified twice-daily administration of AZD6140 in the experimental design. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 2 Prevention of aneurysmal expansion by AZD6140 treatment. Measurement of the external aneurysmal diameter after aneurysm induction at (A) day 10 and (B) day 42. A, The external diameter was similar in control (open squares) and AZD6140-treated rats (solid squares) after 10 days (B) but was significantly lower in the AZD6140 group after 42 days of treatment. C, The increase in aneurysmal diameter was similar for the two groups at day 10 but was significantly reduced in the AZD6140-treated rats (solid bars) at day 42. No increase in aneurysmal diameter was observed between days 10 and 42 for AZD6140-treated rats. Data are presented with the standard deviation. **P < .001. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 3 Inhibition of mural thrombus development by AZD6140 treatment. A, In picrosirius red staining of representative aneurysms from (left) control and (right) AZD6140-treated rats at day 42, the aortic diameter and the thrombus (T) area were greater in aneurysms from control rats compared with AZD6140-treated rats. Note that the deposition of collagen (red staining) within the thrombus is only observed in the AZD6140 group. B, The thrombus area/wall area increased between days 10 and 42 in both groups but was significantly reduced by AZD6140 treatment (solid bars) both at days 10 and 42. C, Intragroup analysis showed that the larger aneurysmal diameter at day 42 was associated with a greater thrombus area (R2 = 0.13 and R2 = 0.40) for control (open circles) and AZD6140-treated rats (solid circles), respectively (P < .05). D, Immunostaining of CD41 (integrin αIIb) within the mural thrombus of aneurysms from (left) control and (right) AZD6140- treated rats at day 42. L, Aortic lumen. Staining quantification shows that treatment for 42 days with AZD6140 significantly decreased the relative size of the CD41-positive area within the mural thrombus compared with the control group. Original magnification ×200. Data are presented with the standard deviation. *P < .05; **P < .01. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 4 Inhibition of inflammatory infiltration by AZD6140 treatment. A, Immunostaining of polymorphonuclear (PMN) leukocytes within the mural thrombus of aneurysms from (left) control and (right) AZD6140-treated rats at day 42. Quantification of PMN leukocyte infiltration within the mural thrombus and the wall is shown at (middle panel) day 10 and (lower panel) day 42. After 10 and 42 days, PMN leukocytes were mostly found within the mural thrombus of control aneurysms (open bars). AZD6140 treatment (solid bars) inhibited the infiltration of PMN leukocytes into the thrombus at both times. B, Immunostaining of macrophages within the mural thrombus of aneurysms from (left) control and (right) AZD6140-treated rats at day 42. Quantification of macrophage infiltration into the mural thrombus and the wall is shown at (middle panel) day 10 and (lower panel) day 42. Macrophages were found within the mural thrombus as well as in the wall of control aneurysms (open bars). After 42 days, more macrophages were present within the wall than in the thrombus. AZD6140 treatment (solid bars) inhibited the infiltration of macrophages within the thrombus at both times. The decrease in macrophage content within the wall after 10 or 42 days of AZD6140 treatment did not reach statistical significance. Data are presented with the standard deviation. L, Aortic lumen. Original magnification ×200. *P < .05; **P < .01. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 5 Decreased matrix metalloproteinase (MMP)-2 activation and MMP-9 expression with AZD6140 treatment. A, Top panel, Representative gelatin zymography shows pro-MMP-2 and active MMP-2 in aneurysms of two controls and AZD6140-treated rats. Middle panel, Pro-MMP-2 and active MMP-2 from control (open bars) and AZD6140-treated rats (solid bars) were quantified by densitometric analysis. *P < .05 vs pro-MMP-2 in AZD6140-treated rats. Bottom panel, Active/pro-MMP-2 ratio represents the pro-MMP-2 activating ability of the tissue. *P < .05. B, MMP-9 immunostaining is shown within the mural thrombus of aneurysms from (left) control and (right) AZD6140-treated rats at day 42. Quantification of MMP-9 staining at day 42 showed that the area occupied by MMP-9 staining relative to the wall area was greater within the thrombus than within the wall in control aneurysms (open bars). AZD6140 treatment strongly reduced the size of the MMP-9-positive area both within the thrombus and the wall (solid bars). Data are presented with the standard deviation. L, Aortic lumen. Original magnification ×200. **P < .001; ***P < .0001. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 6 Smooth muscle cell (SMC) colonization of the mural thrombus and preservation of elastic lamellae within the aneurysmal wall with AZD6140 treatment. A, Orcein staining of aneurysms from (left) control and (right) AZD6140-treated rats at day 42. The arrows indicate the elastic lamellae. Quantification of the elastic lamellae area showed the beneficial effect of AZD6140 treatment (solid bars) at both day 10 and 42. B, Immunostaining of SMCs within the mural thrombus of aneurysms from (left) control and (right) AZD6140-treated rats at day 42. The arrow indicates SMCs within the thrombus. Density of SMCs within the mural thrombus and the wall at (middle panel) day 10 and (bottom panel) day 42 increased between days 10 and 42 in both groups. AZD6140 treatment (solid bars) improved the thrombus colonization by SMCs after 42 days compared with controls (open bars), whereas no effect of AZD6140 could be observed within the wall. Data are presented with the standard deviation. A, Adventitia; L, lumen; M, media. Original magnification ×100. **P < .001. Journal of Vascular Surgery 2009 49, 719-727DOI: (10.1016/j.jvs.2008.09.057) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions