Abstract 2179: Pioglitazone Protected Against Hypertension-based Cerebrovascular Injury in Rats, via the Reduction of Oxidative Stress Derived from NADPH Oxidase
Objective: Very recently, PROspective pioglitAzone Clinical Trial macroVascular Events (PROactive) study shows that pioglitazone reduces the risk of recurrent stroke in type 2 diabetic patients. However, the underlying mechanism of stroke prevention by pioglitazone is unknown. We examined the effect of peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on hypertension-based cerebrovascular injury and incidental stroke in rats.
Methods: Stroke-prone spontaneously hypertensive rats (SHRSP) were orally given to vehicle or pioglitazone (1 mg/kg/day).
We examined the effect of pioglitazone on cerebrovascular injury, brain inflammation, oxidative stress, and vascular endothelial dysfunction induced by hypertension.
We also examined the effect of pioglitazone on incidental stroke of SHRSP, and carefully monitored major stroke-associated symptoms every day for 1 month.
Treatment of SHRSP with pioglitazine for 4 weeks, without affecting blood pressure and blood glucose, improved carotid arterial endothelium-dependent relaxation by acetylcholine (p<0.05 vs vehicle), suppressed the remodeling of middle cerebral artery and brain microvessel (p<0.05), and inhibited brain macrophage infiltration (p<0.05) and the upregulation of brain monocyte chemoattractant protein-1 and tumor necrosis factor-alpha mRNA expressions (p<0.01).
Furthermore, pioglitazone treatment significantly delayed the onset of stroke symptom (p<0.05) and also prolonged survival rate in SHRSP (p<0.05). These beneficial effects of pioglitazone on cerebrovascular injury and stroke in SHRSP were associated with the reduction of brain cortical and vascular superoxide (p<0.01) via the inhibition of NADPH oxidase activity (p<0.05) and NADPH oxidase subunit p22-phox protein levels (p<0.01).
Conclusions: Pioglitazone significantly protected against hypertension-induced cerebrovascular injury and stroke, by improvement of vascular endothelial dysfunction, the inhibition of brain inflammation, and the reduction of oxidative stress. Thus, pioglitazone appears to be the potential therapeutic agent for stroke in type 2 diabetes with hypertension.