Abstract 611: Damage-associated Molecular Pattern (DAMP) Signaling Contributes to Poor Outcomes in Diabetic Ischemic Stroke
Aims: Vascular injury including edema and hemorrhage after ischemic stroke is increased in diabetes. High-mobility group box 1 (HMGB1) is a DAMP passively released by necrotic cells that initiates pro-inflammatory signaling through binding to the TLR4 receptor. Here, we investigated the possible involvement of HMGB1 in increased vascular damage in diabetic ischemic stroke.
Methods and Results: Focal ischemia was induced by 3 h MCAO and 21 h reperfusion in sham (n=6), (Wistar, n=5-7) or diabetic (Goto-Kakizaki, n=6) rats. Expression of HMGB1 and TLR4 was assessed by Western blot in both ischemic and non-ischemic hemispheres. Compared to sham, both control and diabetic rats showed a 2-fold increase in HMGB1 in both non-ischemic and ischemic hemispheres, respectively. While there was no change in TLR4 expression in control rats, it was increased by 2-fold in both hemispheres in diabetes. Neurovascular injury as indicated by percent (%) infarct, edema ratio (edema/infarct), incidence of hematoma and functional outcome were assessed in all groups. Infarct was greater in controls (57.7±5.8% vs. 23±1.0%), while edema ratio was greater in diabetic animals (1.8±0.2 vs. 0.2±0.06). Hematoma was present in the ischemic hemispheres of all diabetic rats and in 43% of the controls. Compared to controls, neurological deficits were greater in diabetic animals after focal ischemia (p<0.05).
Conclusions and clinical relevance: Our findings indicate that HMGB1 and TLR4 may be involved in augmented vascular injury in diabetic ischemic stroke. As such, better understanding of the role(s) of DAMPs including HMGB1 and TLR4 will aid in the development of vasculoprotective therapeutic strategies and improve outcomes for diabetic stroke patients.
- © 2012 by American Heart Association, Inc.