Advertisement

Telmisartan induces proliferation of human endothelial progenitor cells via PPARγ-dependent PI3K/Akt pathway

      Abstract

      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 (PPARγ). 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 PPARγ. 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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Asahara T.
        • Murohara T.
        • Sullivan A.
        • et al.
        Isolation of putative progenitor endothelial cells for angiogenesis.
        Science. 1997; 275: 964-967
        • Kawamoto A.
        • Gwon H.C.
        • Iwaguro H.
        • et al.
        Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia.
        Circulation. 2001; 103: 634-637
        • Kalka C.
        • Masuda H.
        • Takahashi T.
        • et al.
        Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.
        Proc Natl Acad Sci USA. 2000; 97: 3422-3427
        • Schachinger V.
        • Assmus B.
        • Britten M.B.
        • et al.
        Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial.
        J Am Coll Cardiol. 2004; 44: 1690-1699
        • Vasa M.
        • Fichtlscherer S.
        • Aicher A.
        • et al.
        Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.
        Circ Res. 2001; 89: E1-7
        • Hill J.M.
        • Zalos G.
        • Halcox J.P.
        • et al.
        Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.
        N Engl J Med. 2003; 348: 593-600
        • Werner N.
        • Kosiol S.
        • Schiegl T.
        • et al.
        Circulating endothelial progenitor cells and cardiovascular outcomes.
        N Engl J Med. 2005; 353: 999-1007
        • Schmieder R.E.
        Mechanisms for the clinical benefits of angiotensin II receptor blockers.
        Am J Hypertens. 2005; 18: 720-730
        • Benson S.C.
        • Pershadsingh H.A.
        • Ho C.I.
        • et al.
        Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.
        Hypertension. 2004; 43: 1-10
        • Kurtz T.W.
        Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator.
        Acta Diabetol. 2005; 42: S9-16
        • Lehrke M.
        • Lazar M.A.
        The many faces of PPARgamma.
        Cell. 2005; 123: 993-999
        • Li M.
        • Pascual G.
        • Glass C.K.
        Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene.
        Mol Cell Biol. 2000; 20: 4699-4707
        • Jiang C.
        • Ting A.T.
        • Seed B.
        PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.
        Nature. 1998; 391: 82-86
        • Chu K.
        • Lee S.T.
        • Koo J.S.
        • et al.
        Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia.
        Brain Res. 2006; 1093: 208-218
        • Gensch C.
        • Clever Y.P.
        • Werner C.
        • Hanhoun M.
        • Bohm M.
        • Laufs U.
        The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells.
        Atherosclerosis. 2007; 192: 67-74
        • Pistrosch F.
        • Herbrig K.
        • Oelschlaegel U.
        • et al.
        PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells.
        Atherosclerosis. 2005; 183: 163-167
        • Clasen R.
        • Schupp M.
        • Foryst-Ludwig A.
        • et al.
        PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin.
        Hypertension. 2005; 46: 137-143
        • Ouchi N.
        • Kobayashi H.
        • Kihara S.
        • et al.
        Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells.
        J Biol Chem. 2004; 279: 1304-1309
        • Matsuura K.
        • Wada H.
        • Nagai T.
        • et al.
        Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle.
        J Cell Biol. 2004; 167: 351-363
        • Assmus B.
        • Urbich C.
        • Aicher A.
        • et al.
        HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes.
        Circ Res. 2003; 92: 1049-1055
        • Minamino T.
        • Miyauchi H.
        • Yoshida T.
        • Ishida Y.
        • Yoshida H.
        • Komuro I.
        Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.
        Circulation. 2002; 105: 1541-1544
        • Sorrentino S.A.
        • Bahlmann F.H.
        • Besler C.
        • et al.
        Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.
        Circulation. 2007; 116: 163-173
        • Landmesser U.
        • Engberding N.
        • Bahlmann F.H.
        • et al.
        Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase.
        Circulation. 2004; 110: 1933-1939
        • Wada K.
        • Nakajima A.
        • Katayama K.
        • et al.
        Peroxisome proliferator-activated receptor gamma-mediated regulation of neural stem cell proliferation and differentiation.
        J Biol Chem. 2006; 281: 12673-12681
        • Miyauchi H.
        • Minamino T.
        • Tateno K.
        • Kunieda T.
        • Toko H.
        • Komuro I.
        Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway.
        EMBO J. 2004; 23: 212-220
        • Schupp M.
        • Janke J.
        • Clasen R.
        • Unger T.
        • Kintscher U.
        Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity.
        Circulation. 2004; 109: 2054-2057
        • Bahlmann F.H.
        • de Groot K.
        • Mueller O.
        • Hertel B.
        • Haller H.
        • Fliser D.
        Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists.
        Hypertension. 2005; 45: 526-529
        • Min T.Q.
        • Zhu C.J.
        • Xiang W.X.
        • Hui Z.J.
        • Peng S.Y.
        Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease.
        Cardiovasc Drugs Ther. 2004; 18: 203-209
        • Yu Y.
        • Fukuda N.
        • Yao E.H.
        • et al.
        Effect of an ARB on endothelial progenitor cell function and cardiovascular oxidation in hypertension.
        Am J Hypertens. 2008; 21: 72-77
        • You D.
        • Cochain C.
        • Loinard C.
        • et al.
        Combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide activate postnatal vasculogenesis in spontaneously hypertensive rats.
        J Pharmacol Exp Ther. 2008; 325: 766-773
        • Imanishi T.
        • Hano T.
        • Nishio I.
        Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress.
        J Hypertens. 2005; 23: 97-104
        • Mehta P.K.
        • Griendling K.K.
        Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.
        Am J Physiol Cell Physiol. 2007; 292: C82-C97
        • Fujimoto M.
        • Masuzaki H.
        • Tanaka T.
        • et al.
        An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.
        FEBS Lett. 2004; 576: 492-497
        • Sugimoto K.
        • Qi N.R.
        • Kazdová L.
        • Pravenec M.
        • Ogihara T.
        • Kurtz T.W.
        Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis.
        Hypertension. 2006; 47: 1-7
        • Yoshida T.
        • Yamagishi S.
        • Nakamura K.
        • et al.
        Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation.
        Diabetologia. 2006; 46: 1698-1705
        • Nakaya K.
        • Ayaori M.
        • Hisada T.
        • et al.
        Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma.
        J Atheroscler Thromb. 2007; 14: 133-141
        • Mori Y.
        • Itoh Y.
        • Tajima N.
        Angiotensin II receptor blockers downsize adipocytes in spontaneously type 2 diabetic rats with visceral fat obesity.
        Am J Hypertens. 2007; 20: 431-436
        • Goetze S.
        • Xi X.P.
        • Kawano H.
        • et al.
        PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells.
        J Cardiovasc Pharmacol. 1999; 33: 798-806
        • Delerive P.
        • Martin-Nizard F.
        • Chinetti G.
        • et al.
        Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway.
        Circ Res. 1999; 85: 394-402
        • Imanishi T.
        • Kobayashi K.
        • Kuroi A.
        • Ikejima H.
        • Akasaka T.
        Pioglitazone inhibits angiotensin II-induced senescence of endothelial progenitor cell.
        Hypertens Res. 2008; 31: 757-765
        • Dimmeler S.
        • Aicher A.
        • Vasa M.
        • et al.
        HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway.
        J Clin Invest. 2001; 108: 391-397
        • Gao N.
        • Zhang Z.
        • Jiang B.H.
        • Shi X.
        Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer.
        Biochem Biophys Res Commun. 2003; 310: 1124-1132
        • Rossig L.
        • Jadidi A.S.
        • Urbich C.
        • Badorff C.
        • Zeiher A.M.
        • Dimmeler S.
        Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells.
        Mol Cell Biol. 2001; 21: 5644-5657
        • Wang C.H.
        • Ciliberti N.
        • Li S.H.
        • et al.
        Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy.
        Circulation. 2004; 109: 1392-1400
        • Marchetti V.
        • Menghini R.
        • Rizza S.
        • et al.
        Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling.
        Diabetes. 2006; 55: 2231-2237
        • Polikandriotis J.A.
        • Mazzella L.J.
        • Rupnow H.L.
        • Hart C.M.
        Peroxisome proliferator- activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma dependent mechanisms.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1810-1816
        • Rosso A.
        • Balsamo A.
        • Gambino R.
        • et al.
        p53 Mediates the accelerated onset of senescence of endothelial progenitor cells in diabetes.
        J Biol Chem. 2006; 281: 4339-4347
        • Bonofiglio D.
        • Aquila S.
        • Catalano S.
        • et al.
        Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells.
        Mol Endocrinol. 2006; 20: 3083-3092
        • Gartel A.L.
        • Radhakrishnan S.K.
        Lost in transcription: p21 repression, mechanisms, and consequences.
        Cancer Res. 2005; 65: 3980-3985
        • Stangier J.
        • Su C.A.
        • Roth W.
        Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients.
        J Int Med Res. 2000; 28: 149-167
        • Hirschi K.K.
        • Ingram D.A.
        • Yoder M.C.
        Assessing identity, phenotype, and fate of endothelial progenitor cells.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1584-1595
        • Urbich C.
        • Heeschen C.
        • Aicher A.
        • Dernbach E.
        • Zeiher A.M.
        • Dimmeler S.
        Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells.
        Circulation. 2003; 108: 2511-2516
        • Rehman J.
        • Li J.
        • Orschell C.M.
        • March K.L.
        Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors.
        Circulation. 2003; 107: 1164-1169
        • Yoon C.H.
        • Hur J.
        • Park K.W.
        • et al.
        Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases.
        Circulation. 2005; 112: 1618-1627
        • Ingram D.A.
        • Caplice N.M.
        • Yoder M.C.
        Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells.
        Blood. 2005; 106: 1525-1531
        • Case J.
        • Mead L.E.
        • Bessler W.K.
        • et al.
        Human CD34+ AC133+ VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors.
        Exp Hematol. 2007; 35: 1109-1118