Inflammation and vulnerable blood vessels aggravate ischemic injuries in a mouse model of Type 1 diabetes

Abstract

PURPOSE: Patients with type 1 diabetes are more prone to cerebrovascular mortality after stroke and display a more severe post-ischemic outcome. Their median survival is only half when compared with those in the general population. In the current study, we aim to elucidate the potential mechanisms contributing to the exacerbation. METHOD: Ins2Akita/+ mice, a type 1 diabetic mouse model, and their wildtype (Ins2+/+) littermates at 12 weeks of age were challenged with experimental stroke by middle cerebral artery occlusion (MCAO) for 2h followed by 2h of reperfusion. Survival rate and neurological deficits were assessed at the end of reperfusion. Their brain slices were stained with 2, 3, 5-triphenyltetrazolium chloride for estimation of the infarction, hemispheric swelling and hemorrhagic area. Western blot analysis was used to compare levels of ZO-1, VEGF and pErk for assessment of blood vessel integrity and inflammation. ER-stress (ATF6, BiP, CHOP, PERK and IRE-1α) and autophagy (Atg12, Bcn1, LC3-a, LC3-b and p62) response were also assayed using real-time PCR. RESULTS: Decreased survival rate, increased neurological deficits as well as increased infarct and hemorrhage after MCAO were observed in Ins2Akita/+ mice. There were also significant down-regulation of ZO-1 protein and remarkable up-regulation of VEGF and pErk protein. mRNA expression of CHOP was further augmented in Ins2Aktia/+ mice. CONCLUSION: Ins2Akita/+ mice displayed high mortality after MCAO, similar to that in type 1 diabetic patients upon stroke. Augmented cerebral hemorrhage and decreased ZO-1 expression indicated a lower blood vessel integrity in Ins2Akita/+ mice. Provoked inflammatory response and ER-stress may play important roles in the exacerbation of the ischemic brain, which was evidenced in increased infarction in Ins2Akita/+ mice.