Abstract: SA-PO292

Lipoxins Attenuate Diabetic Complications in the ApoE-/- Mouse

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Brennan, Eoin P., University College Dublin, Dublin, Ireland
  • Cooper, Mark E., Monash University, Melbourne, Victoria, Australia
  • Kantharidis, Phillip, Monash University, Melbourne, Victoria, Australia
  • Godson, Catherine, University College Dublin, Dublin, Ireland
  • Mohan, Muthukumar, Monash University, Melbourne, Victoria, Australia
  • De gaetano, Monica, University College Dublin, Dublin, Ireland
  • Tikellis, Chris, Monash University, Melbourne, Victoria, Australia
  • Marai, Mariam, University College Dublin, Dublin, Ireland
  • Ziemann, Mark, Monash University, Melbourne, Victoria, Australia
  • Belton, Orina, University College Dublin, Belfield, Dublin, Ireland
  • El-Osta, Assam, Monash University, Melbourne, Victoria, Australia
  • Jandeleit-Dahm, Karin, Monash University, Melbourne, Victoria, Australia
Background

Targeting both inflammation and fibrosis in diabetes-related complications has proven elusive. Endogenous lipid mediators including Lipoxins (LXs) actively promote the resolution of inflammatory responses. We investigated the potential of Lipoxin A4 (LXA4), an endogenously produced mediator that promotes the resolution of inflammation, and a synthetic lipoxin 15(R)-Benzo-LXA4 as experimental therapeutics in the streptozotocin-induced diabetic ApoE-/- mouse, a model of diabetic complications.

Methods

Diabetes was induced with low-dose streptozotocin (55mg/kg). Following 10 weeks of diabetes progression, mice were administered either vehicle (0.1% ethanol), LXA4 (5ug/kg), or Benzo-LXA4 analogue (1.7ug/kg) for 6 additional weeks.

Results

LXs attenuated kidney disease, with evidence of reduced albuminuria (Diabetes+Vehicle: 25.1±2.1 µg/24h vs Diabetic+LXA4: 17.3±2.4 µg/24h), glomerular expansion, and collagen deposition. RNA-Seq transcriptome profiling identified the diabetic renal gene signature (725 genes) and subsets regulated by LXs. Pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (EGR-1) networks regulated by LXs. LXs also reduced aortic atherosclerotic plaque development and pro-inflammatory signaling pathways in vascular tissue. LXs attenuated vascular smooth muscle cell proliferation and migration, and inhibited monocyte-endothelial cell adhesion. Treatment of human carotid plaques ex vivo with LXA4 attenuated secretion of pro-inflammatory cytokines including IFN-γ, IL-1β and TNF-α, thereby highlighting the potential clinical relevance of LX-based therapeutics. Finally, we have previously identified the let-7 miRNA family as important mediators of renal fibrosis, and here we demonstrate that restoration of let-7 levels in aortic vascular tissues could provide a new target for an anti-inflammatory approach in diabetic vascular disease.

Conclusion

In conclusion, these data support a novel pro-resolution therapeutic approach for treating and preventing concomitantly multiple vascular complications of diabetes.

Funding

  • Government Support - Non-U.S.