Abstract 5501: Enlarged Ischemic Damage and Decreased SDF-1a Expression in the Brain of db/db Diabetic Mice
Introduction: Stromal cell derived factor-1a (SDF-1a) and its specific receptor Cysteine-X-Cysteine receptor 4 (CXCR4) together forms an important regulatory axis of angiogenesis and tissue repair after ischemia. Emerging evidence suggests that dysfunction of SDF-1a/CXCR4 axis may be responsible for impairment of angiogenesis and delayed wound healing in type 2 diabetes mellitus. The type 2 diabetes mellitus is a major risk for ischemic stroke. However, there are questions as to whether SDF-1a/CXCR4 axis is involved in ischemic stroke in diabetes. In this study, we determined the effect of diabetes on ischemic stroke and regulation of SDF-1a in brain.
Methods and Results: Male db/db mice (8 weeks) and age-matched db/+ control mice were used (glucose 524.1±10.2 vs. 179.7±16.5 mg/dl, db/db vs. db/+, n=16, p<0.01). Focal ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery and the cerebral damage was determined 48 hrs after surgery by triphenyltetrazolium chloride (TTC) staining. Cerebral microvascular density in the frontal cortex was measured by immunostaining for CD31. The expression of SDF-1a in ischemic (48 hrs after MCAO) and non-ischemic (contra-lateral to MCAO side) brain was determined using western blot and real-time RT-PCR methods. We found:
Ischemic damage volume was much increased in db/db mice (28.6±2.2% and 16.5±1.5%, db/db vs. db/+, n=6, p< 0.01);
Microvascular density in the cortex of db/db mice was reduced as compared with db/+ mice (338±29 vs. 416±32 capillaries/mm2, db/db vs. db/+, n=4, p< 0.05);
SDF-1a expression was down-regulated in the non-ischemic brain of db/db mice (db/db vs. db/+, real-time RT-PCR: 63±9% vs. 100±16%, n=5, p< 0.01; western blot: 0.15±0.02 vs. 0.19±0.02, n=6, p< 0.05);
There was also less up-regulation of SDF-1a in the ischemic brain of db/db mice (db/db vs. db/+, real-time RT-PCR:175±24% vs. 400±43%, n=5, p< 0.01; western blot: 0.23±0.02 vs. 0.29±0.02, n=6, p< 0.05).
Conclusion: Impaired SDF-1a regulation and reduced microvascular density may be linked to enlarged ischemic cerebral damage and a potential therapeutic target for ischemic stroke in diabetes.
This research has received full or partial funding support from the American Heart Association, National Center.