Rosiglitazone via upregulation of Akt/eNOS pathways attenuates dysfunction of endothelial progenitor cells, induced by advanced glycation end products

Abstract

Background and purpose: Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play key roles in pathogenesis of diabetes-related vascular complications. AGEs can induce dysfunction in EPCs. The peroxisome proliferatoractivated receptor-gamma (PPARg) agonists are widely used in the treatment of type 2 diabetes, and it remains unknown if they could attenuate EPC dysfunction induced by AGEs. Experimental approach: EPCs isolated from healthy adults were cultured with various concentrations of AGEs (0, 50, 100 and 200 mg·L -1 ) with or without rosiglitazone (10 nM), antibody for the receptors for AGE-human serum albumin (anti-receptor for advanced glycation end products (RAGE); 50 mg·mL -1 ), phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002, 5 mM), nitric oxide (NO) synthase inhibitor (L-N G -nitro-arginine methyl ester (L-NAME), 100 mM) or sodium nitroprusside (SNP, 25 mM). Proliferation, apoptosis, cell adhesion, migration and NO production in EPCs were assessed, and expressions of endothelial NO synthase (eNOS) and Akt were determined. Key results: Number, proliferation/migration capacities, eNOS and Akt phosphorylation as well as NO synthesized by EPCs were increased by rosiglitazone and reduced by AGEs. AGEs promoted while rosiglitazone reduced EPC apoptosis. The AGE-induced effects were significantly ameliorated by pre-incubation with rosiglitazone, RAGE antibody and SNP. The beneficial effects of rosiglitazone could be blocked by pretreatment with L-NAME and LY294002. Conclusions and implications:The PPARg agonist rosiglitazone increased EPC function and attenuated EPC dysfunction induced by AGEs via upregulating the Akt-eNOS signal pathways of EPCs.

Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal Pathways

“…Furthermore, rosiglitazone increased EPC survival, differentiation, and function, which were impaired by C-reactive protein (CRP) (26). Another study reported that rosiglitazone ameliorated AGE-induced dysfunction of EPCs via activation of the PI3K-Akt-eNOS signal pathway (27). However, the current findings of mechanisms of rosiglitazone on EPCs mainly included activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of the NAD(P)H oxidase activity of progenitor cells.…”

The PPARγ Agonist Protects Cardiomyocytes from Oxidative Stress and ApoptosisviaThioredoxin Overexpression

“…Besides glucose control, RSG shows diverse therapeutic effects in the regulation of endothelial function, cellular apoptosis, tissue fibrosis, and the control of blood pressure. [28][29][30][31][32] In addition, it limits cardiac hypertrophy in diet-induced hypercholesterolemic rats by the renin-angiotensin system. 16) Furthermore, current evidence suggests that it has beneficial effects on CMCs under oxidative stress.…”

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…For instance, the peroxisome proliferator-activated receptors y (PPARgamma) agonist rosiglitazone increased EPC function via upregulating the AkteNOS signal pathways (58). Pioglitazone increased EPC adhesion to arteries from diabetic patients via an upregulation CIRCULATING ANGIOGENIC CELL DYSFUNCTIONof CXCR4, the receptor for SDF-1.…”