Abstract 223: Telmisartan Induce The Proliferation Of Human Peripheral Endothelial Progenitor Cells Via PPARγ Dependent PI3K/Akt Pathway
The stimulation of proliferation of EPCs is thought to be the useful preventive and therapeutic strategy for cardiovascular diseases. Recently, telmisartan (Tel), an angiotensin II receptor blocker, has been reported to have the PPARγ activity. The aim of this study is to elucidate the effect of telmisartan on the proliferation of EPCs. Human peripheral blood mononuclear cells were isolated from the healthy volunteers and cultured on the fibronectin coated dish with telmisartan. 4 days after starting culture, the number of adherent cells, which were double positive for DiI-AcLDL and lectin, was significantly increased in telmisartan treatment group compared to control. About 80–90% of these cells were also positive for VEGFR-2 and VE-cadherin. Next these cells were collected and equal number of cells was reseeded into methylcellulose plates. 7 days after starting culture, interestingly telmisartan significantly increased the number of colonies with the dose dependent manner (control; 4.5 ± 0.9, 1 μM; 18.3 ± 5.5, 10 μM; 20.3 ± 5.6, p < 0.05, n = 4) and these colonies were double positive for DiI-AcLDL and lectin, suggesting that telmisartan induced the proliferation of EPCs. This increase of colony by the treatment with telmisartan was absolutely abolished when treated with GW9662 (GW), a specific inhibitor of PPARγ (Tel; 28.4 ± 5.5 versus Tel + GW; 10.8 ± 2.0: p < 0.05, n = 5). The number of EPCs colonies was significantly decreased when treated with PI3K inhibitors including Ly294002 and wortmannin. Furthermore, phosphorylation of Akt was significantly upregulated after the treatment with telmisartan. The percentage of senescence associated (SA) β-gal positive cells did not change between control and 1 μM telmisartan treatment group (control; 30.7 ± 2.0 %, 1 μMTel; 27.8 ± 1.1 %, n = 6). however, when treated with a high dose (10 μM) of telmisartan, the percentage of SA β-gal-positive cells was significantly increased compared to control (10 μM Tel: 51.8 ± 2.2%, n = 3, p < 0.01), suggesting that high doses of telmisartan induced cellular senescence of EPCs, but middle doses did not. These findings suggest telmisartan induce the proliferation of EPCs via PPARγ dependent PI3K/Akt signaling pathway and PPARγ might be the important target of neovascularization.