OBJECTIVE: Although recent
clinical trials have suggested that
angiotensin II type 1 receptor blockers (ARBs) reduced
cardiovascular events, the precise mechanisms involved are still unknown.
Telmisartan, an ARB, has recently been identified as a ligand of
peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other
hand, since
endothelial progenitor cells (EPCs) are thought to play a critical role in
ischemic diseases, we investigated effects of
telmisartan on proliferation of EPCs. METHODS AND RESULTS: Human
peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of
telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into
methylcellulose medium with or without
telmisartan. In the presence of
telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and
lectin and
CD31,
CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with
telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARgamma. In addition, we observed that specific inhibitors of phosphoinositide-3
kinase (
PI3K) abolished telmisartan-stimulated increase of
monocytic EPC-like cells and
telmisartan induced
phosphorylation of
Akt. Furthermore,
mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth
inductive effects of
telmisartan might be regulated by the
PI3K/
Akt and p21
signaling pathway. CONCLUSIONS: These findings suggest that
telmisartan might contribute to
endothelial integrity and
vasculogenesis in
ischemic regions by increasing numbers of EPCs.
