Telmisartan induces proliferation of human endothelial progenitor cells via PPARγ-dependent PI3K/Akt pathway
Introduction
Promotion of neovascularization aims to rescue ischemic tissues. Although angiogenesis, a process involving proliferation and migration of preexisting endothelial cells was thought to be the main mechanism of postnatal neovascularization, recent evidence shows that bone marrow-derived circulating endothelial progenitor cells (EPCs) partly contribute to this mechanism [1]. Injections of bone marrow-derived EPCs to ischemic tissues have been reported to result in new blood vessel formation, and to protect tissues from ischemic damages [2], [3]. In addition to animal model experiments, clinical trials demonstrate that intracoronary injection of EPCs improves left ventricular ejection fraction and end systolic volumes [4]. Numbers of atherosclerotic risk factors have been reported to correlate with reduced numbers of circulating EPCs [5]. Furthermore, increases in numbers and colonies of EPCs have been reported to predict beneficial occurrence of cardiovascular events and death from cardiovascular causes [6], [7]. Therefore, stimulation of proliferation of circulating EPCs might be a useful novel preventive and therapeutic strategy for the treatment of ischemic cardiovascular diseases.
Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension, ischemic heart disease and heart failure. ARBs have been reported to have protective effects on the cardiovascular system beyond blood pressure lowering effect in many clinical trials [8]. Telmisartan, one of the ARBs, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARγ) [9], [10]. PPARs are transcription factors belonging to the nuclear receptor superfamily that heterodimerizing with the retinoid X receptor and bind to PPAR responsive elements in target gene promoters [11]. Thiazolidinediones (TZDs) have been proposed to ameliorate insulin resistance by binding to and activating PPARγ in adipose tissue, thereby promoting adipose differentiation and increasing the number of small adipocytes that are more sensitive to insulin. Besides the effects on insulin resistance, TZDs are known to be capable of reducing vascular inflammation [12], [13]. TZDs have recently been shown to promote new blood vessel formation in a cerebral ischemic model [14]. Furthermore, recent reports showed that pioglitazone and rosiglitazone, included in TZDs, increased the number of EPCs with unknown mechanisms [15], [16]. Telmisartan induces adiponectin expression via PPARγ activation [17], and adiponectin has been reported to induce angiogenesis [18]. But the direct evidences of telmisartan on angiogenesis have not been reported. To elucidate the mechanisms involved in neovascularization by telmisartan, we investigated effects of telmisartan on EPCs, and the underlying signaling pathway.
In this study, we showed that telmisartan induced proliferation of human peripheral blood-derived EPCs in vitro via the phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway, and telmisartan affected cellular senescence of EPCs.
Section snippets
Reagents
The following reagents and antibodies were used: valsartan (The United States Pharmacopeia, Rockville, MD), GW9662 (Sigma Aldrich, St. Louis. MO), Ly294002 (CALBIOCHEM, San Diego, CA), human VEGF (R&D systems, Minneapolis, MN), mouse monoclonal antibodies against human vascular endothelium (VE)-cadherin (Beckman coulter, France), mouse monoclonal anti-human CD14 antibody (CHEMICON, Australia), mouse monoclonal anti-human CD31 (PECAM-1) antibody (R&D systems, Minneapolis, MN), mouse monoclonal
Telmisartan induces the proliferation of monocytic EPC-like cells and EPCs
First, we isolated the peripheral blood mononuclear cells from healthy human volunteers and cultured these cells on the fibronectin-coated dishes in endothelial growth medium. Four days after starting culture, adherent and spindle-shaped cells were recognized. Almost all of these adherent cells were positive for DiI-AcLDL uptake, FITC-conjugated UEA-1 lectin binding (Fig. 1a). To further characterize these adherent cells, we compared the expression of CD14 and CD45 between adherent cells and
Discussion
In this paper, we demonstrated, for the first time, that telmisartan induced proliferation of human EPCs via PPARγ-dependent PI3K/Akt signaling pathway in vitro.
Recently, telmisartan has been identified as a partial agonist of PPARγ. The other clinically approved ARBs appear to have relatively little or no effect on PPARγ activity, with the exception of irbesartan and a metabolite of losartan, both of which are much less potent activators of PPARγ than telmisartan [9], [26]. So far, it has been
Conflict of interest
The authors declare that they have no competing financial interests.
Acknowledgements
This study was supported in part by a Grant-in-Aid for Scientific Research, Developmental Scientific Research, and Scientific Research from the Ministry of Education, Science, Sports, and Culture (to K.M.).
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