Lipoxins protect against inflammation in diabetes-associated atherosclerosis

Eoin P. Brennan, Muthukumar Mohan, Aaron McClelland, Monica De Gaetano, Christos Tikellis, Mariam Marai, Daniel Crean, Aozhi Dai, Ophelie Beuscart, Sinda Derouiche, Stephen P. Gray, Raelene Pickering, Sih Min Tan, Molly Godson-Treacy, Stephen Sheehan, Joseph F. Dowdall, Mary Barry, Orina Belton, Syed Tasadaque Ali-Shah, Patrick J. Guiry & 4 others Karin Jandeleit-Dahm, Mark E. Cooper, Catherine Godson, Phillip Kantharidis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE2/2 mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE2/2 mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 6 2.01% [diabetic]; 12.67 6 1.68% [diabetic + LXA4]; 13.19 6 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.

Original languageEnglish
Pages (from-to)2657-2667
Number of pages11
JournalDiabetes
Volume67
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Brennan, Eoin P. ; Mohan, Muthukumar ; McClelland, Aaron ; De Gaetano, Monica ; Tikellis, Christos ; Marai, Mariam ; Crean, Daniel ; Dai, Aozhi ; Beuscart, Ophelie ; Derouiche, Sinda ; Gray, Stephen P. ; Pickering, Raelene ; Tan, Sih Min ; Godson-Treacy, Molly ; Sheehan, Stephen ; Dowdall, Joseph F. ; Barry, Mary ; Belton, Orina ; Ali-Shah, Syed Tasadaque ; Guiry, Patrick J. ; Jandeleit-Dahm, Karin ; Cooper, Mark E. ; Godson, Catherine ; Kantharidis, Phillip. / Lipoxins protect against inflammation in diabetes-associated atherosclerosis. In: Diabetes. 2018 ; Vol. 67, No. 12. pp. 2657-2667.
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title = "Lipoxins protect against inflammation in diabetes-associated atherosclerosis",
abstract = "Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE2/2 mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE2/2 mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 6 2.01{\%} [diabetic]; 12.67 6 1.68{\%} [diabetic + LXA4]; 13.19 6 1.97{\%} [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.",
author = "Brennan, {Eoin P.} and Muthukumar Mohan and Aaron McClelland and {De Gaetano}, Monica and Christos Tikellis and Mariam Marai and Daniel Crean and Aozhi Dai and Ophelie Beuscart and Sinda Derouiche and Gray, {Stephen P.} and Raelene Pickering and Tan, {Sih Min} and Molly Godson-Treacy and Stephen Sheehan and Dowdall, {Joseph F.} and Mary Barry and Orina Belton and Ali-Shah, {Syed Tasadaque} and Guiry, {Patrick J.} and Karin Jandeleit-Dahm and Cooper, {Mark E.} and Catherine Godson and Phillip Kantharidis",
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Brennan, EP, Mohan, M, McClelland, A, De Gaetano, M, Tikellis, C, Marai, M, Crean, D, Dai, A, Beuscart, O, Derouiche, S, Gray, SP, Pickering, R, Tan, SM, Godson-Treacy, M, Sheehan, S, Dowdall, JF, Barry, M, Belton, O, Ali-Shah, ST, Guiry, PJ, Jandeleit-Dahm, K, Cooper, ME, Godson, C & Kantharidis, P 2018, 'Lipoxins protect against inflammation in diabetes-associated atherosclerosis' Diabetes, vol. 67, no. 12, pp. 2657-2667. https://doi.org/10.2337/db17-1317

Lipoxins protect against inflammation in diabetes-associated atherosclerosis. / Brennan, Eoin P.; Mohan, Muthukumar; McClelland, Aaron; De Gaetano, Monica; Tikellis, Christos; Marai, Mariam; Crean, Daniel; Dai, Aozhi; Beuscart, Ophelie; Derouiche, Sinda; Gray, Stephen P.; Pickering, Raelene; Tan, Sih Min; Godson-Treacy, Molly; Sheehan, Stephen; Dowdall, Joseph F.; Barry, Mary; Belton, Orina; Ali-Shah, Syed Tasadaque; Guiry, Patrick J.; Jandeleit-Dahm, Karin; Cooper, Mark E.; Godson, Catherine; Kantharidis, Phillip.

In: Diabetes, Vol. 67, No. 12, 01.12.2018, p. 2657-2667.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gray, Stephen P.

AU - Pickering, Raelene

AU - Tan, Sih Min

AU - Godson-Treacy, Molly

AU - Sheehan, Stephen

AU - Dowdall, Joseph F.

AU - Barry, Mary

AU - Belton, Orina

AU - Ali-Shah, Syed Tasadaque

AU - Guiry, Patrick J.

AU - Jandeleit-Dahm, Karin

AU - Cooper, Mark E.

AU - Godson, Catherine

AU - Kantharidis, Phillip

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE2/2 mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE2/2 mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 6 2.01% [diabetic]; 12.67 6 1.68% [diabetic + LXA4]; 13.19 6 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.

AB - Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE2/2 mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE2/2 mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 6 2.01% [diabetic]; 12.67 6 1.68% [diabetic + LXA4]; 13.19 6 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.

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Brennan EP, Mohan M, McClelland A, De Gaetano M, Tikellis C, Marai M et al. Lipoxins protect against inflammation in diabetes-associated atherosclerosis. Diabetes. 2018 Dec 1;67(12):2657-2667. https://doi.org/10.2337/db17-1317