Hemin prevents in-stent stenosis in rat and rabbit models by inducing heme-oxygenase- 1 Jean-Marc Hyvelin, PhD, Blandine Maurel, MSc, MD, Rustem Uzbekov,

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Presentation transcript:

Hemin prevents in-stent stenosis in rat and rabbit models by inducing heme-oxygenase- 1 Jean-Marc Hyvelin, PhD, Blandine Maurel, MSc, MD, Rustem Uzbekov, PhD, Roberto Motterlini, PhD, Patrick Lermusiaux, MD Journal of Vascular Surgery Volume 51, Issue 2, Pages 417-428 (February 2010) DOI: 10.1016/j.jvs.2009.09.004 Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 1 Study flow chart for (A) rat model and (B) hypercholesteremic rabbit model. BMS, Bare-metal stent; CORM-3, (tricarbonylchloro(glycinato)ruthenium[II]; DES, sirolimus drug-eluting stent; EM, electron microscopy; LM, light microscopy; SnPP, tin-protoporphyrin; WB, Western blotting. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 2 Effect of hemin treatment on in-stent stenosis is shown in rats and hypercholesterolemic rabbits. A, Rat aorta morphology 28 days after stenting. The bar graph shows the n/m ratio in control (n = 8), hemin-treated (n = 8), and aortas stented with sirolimus drug-eluting stents (DES, n = 3). The scatter graph indicates the standard deviation (SD) of the n/m ratio of each stented aortic segment from control and hemin-treated rats. SD was derived from the average of the 15 to 25 analyzed sections per stent and used as an index of the variability of stenosis within each stent. B, Angiography of the rabbit aortoiliac bifurcation 28 days after stent deployment is shown in the top panel. The insert shows higher magnification of the red box. The daggers indicate stenosis. The morphology of the iliac stented arteries (red box) is presented in the bottom panel. The bar graph shows the n/m ratio in control (n = 7), hemin-treated (n = 8), and sirolimus-DES stented iliac arteries (n = 3). The results are the mean ± standard error of the mean. The scatter graph indicates the SD of the n/m ratio of each stented iliac arteries. Significant difference from control: *P < .05, **P < .005. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 3 A, Transmission electron microscopic (TEM) analysis of the endothelialization of stented arteries is shows neointima (n) around the stent strut (s) in the control and hemin-treated rats (original magnification ×875). Higher magnification (×5000) of the cells at the interface of the lumen (L) shows ultrastructure similar to that of endothelial cells. The arrows indicate tight junctions. B, Immunogold labeling of CD31 on cells facing the arterial lumen in hemin-treated rats. The top panel shows neointima above stent strut. Higher magnification of the black box is presented below and shows positive labeling of CD31 on the selected cell. The schematic diagram shows a two-dimensional reconstruction of the selected cell from five consecutive ultrathin sections. C, Scanning electron microscopy (SEM) shows endothelial coverage of the stented aorta. The inserts show SEM at a lower magnification of the stented arteries. The bar graph shows the mean endothelial coverage in the control and hemin-treated groups (n = 8 per group). The error bars show the standard error of the mean. D, TEM shows the neointima (n) around the stent strut (s) in rabbit iliac arteries. The inserts show SEM at a lower magnification of the stented arteries. The bar graph indicates neointima thickness above the stent struts (n = 4 in each groups). The error bars show the standard error of the mean. **Significantly different from control (P < .005). E, SEM shows endothelial coverage of the stented iliac artery. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 4 Effect of hemin treatment on protein expression in rat aortas 7 days after stenting. A, Protein array of inflammatory cytokines in control (n = 4) and hemin-treated (n = 4) rats. The results are the mean ± standard error of the mean. B, Typical Western blot of proteins from stented aortas of control and hemin-treated rats. Each lane represents one rat. C, Protein levels were quantified by densitometry and normalized with respect to α-actin. Activities of p42/44 and RhoA were expressed as the ratio of phosphorylated p42/44 to total p42/44 and the ratio of guanosine triphosphate (GTP)-bound RhoA to total RhoA, respectively. The results are the mean ± standard error of the mean (n = 5 each group). Significant difference from control: *P < .05, **P < .005. HO-1, heme oxygenase-1; IL, interleukin; INFα, interferon-α; IP-10, interferon-inducible protein 10; MIP, macrophage inflammatory protein; RANTES, regulated upon activation normal T-cell expressed and secreted; sICAM, soluble intercellular adhesion molecule 1; TNF, tumor necrosis factor. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 5 Effect of hemin treatment on protein expression is shown in rat aortas 28 days after stenting. A, In this typical Western blot of proteins from stented aortas of control and hemin-treated rats, each lane represents one rat. B, Densitometry analysis shows heme oxygenase-1 (HO-1) expression and cleaved caspase 3. C, Protein levels are shown for the regulators of cell proliferation. The upper panel shows the expression of the Ki-67 protein, assessed by Western blot analysis (left) and immunofluorescence (right). Immunofluorescence shows better expression of the Ki-67 protein in the control group. Negative controls are presented below. The lower panel shows the expression of the p21, p27kip1, p42/44, and RhoA. The results are the mean ± standard error of the mean of five rats in each group. Significant difference from control: *P < .05, **P < .005. GTP, Guanosine triphosphate. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 6 Effect of chronic treatment with tin-protoporphyrin IX (SnPPIX) and tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) on in-stent stenosis in rat aorta. A, Aorta morphology 28 days after stenting in the control, SnPPIX (15 mg/kg), SnPPIX plus hemin (50 mg/kg, each), and CORM-3 rats (30 mg/kg; n = 5 all groups). The bar graph represents mean n/m ± standard error of the mean. The plasma bilirubin levels in the different groups are presented below. Significant difference from control: *P < .05, **P < .005). B, Effect of pharmacologic treatments on in-stent stenosis in rat aortas and rabbit iliac arteries. Results are expressed as percentage change of n/m when compared with control groups. The results are the mean ± standard error of the mean. Journal of Vascular Surgery 2010 51, 417-428DOI: (10.1016/j.jvs.2009.09.004) Copyright © 2010 Society for Vascular Surgery Terms and Conditions