Abstract
BackgroundType 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-γ (PPARγ) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering.MethodsBy using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARγ, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARγ inhibitor GW9662.ConclusionThese data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARγ independent manner.
Highlights
Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications
The treatment with GW1929 did not exert any effect on ischemic muscle (Fig. 1b), on Vascular Endothelial Growth Factor (VEGF) expression (Fig. 3) and on blood flow recovery, while pioglitazone maintained its activity in normalizing the expression of VEGF (Fig. 3), activating Akt and restoring blood flow in mice where Peroxisome proliferatoractivated receptor-γ (PPARγ) was inhibited by GW9662 (Fig. 1a). These results suggest that pioglitazone presides its favorable effects on ischemic-induced angiogenesis regardless of PPARγ activity
These data demonstrate that Akt pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARγ independent manner
Summary
Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Thiazolidinedione derivatives (TZDs), such as pioglitazone, troglitazone and rosiglitazone, are indicated for therapy of type 2 diabetes mellitus (T2DM). They have been demonstrated to be effective alone or in combination with a sulfonylurea, metformin, or insulin. In addition to its insulin sensitizing effects, increasing evidence suggests that this drug improve vascular health, vascular function and inflammatory biomarkers of arteriosclerosis [10,11,12] These vascular effects seem to occur independently of glucose lowering and have been demonstrated in nondiabetic, healthy individuals [10,12,13,14]. These findings have led to the hypothesis that pioglitazone could exert vasculoprotective effects that are independent of its metabolic action
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