Effects of the antioxidative beta-blocker celiprolol on endothelial progenitor cells in hypertensive rats.

BACKGROUND Endothelial progenitor cells (EPCs) derived from bone marrow migrate to areas of endothelial damage and repair them. EPC function is impaired by oxidative stress. We examined the effects of an antioxidative beta1-adrenoceptor blocker on the number and function of EPCs in hypertensive rats. METHODS Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were fed diets loaded with high salt. The SHRs were treated with celiprolol or atenolol for 2 weeks. Peripheral blood mononuclear cells (MNCs) were separated, subjected to flow cytometric analysis to determine the number of circulating EPCs, and cultured to quantify EPC colony formation. EPC migration was evaluated in migration assay chambers. EPC senescence was evaluated using beta-galactosidase assay. Oxidative stress of EPCs was evaluated using thiobarbituric acid-reactive substance (TBARS) assay. The expression of nicotinamine adenine dinucleotide phosphate (NAD(P)H) oxidase component mRNAs in the renal cortex, aorta, and heart were evaluated by real-time PCR. RESULTS The number, colony formation, and migration of EPCs in SHRs were significantly lower than those in WKY rats. TBARS scores in EPCs from SHRs were significantly higher than those from WKY rats. Celiprolol increased the number of circulating EPCs and stimulated EPC colony formation and migration, while decreasing EPC senescence. Celiprolol inhibited oxidation in EPCs from SHRs, and decreased the expression of NAD(P)H oxidase component mRNAs in the renal cortex, aorta, and heart. CONCLUSION EPCs are impaired in SHRs in response to oxidative stress. Celiprolol decreases oxidative stress in hypertension in vivo and improves EPC numbers and function. It appears, therefore, that celiprolol may exert beneficial cardiovascular effects through its antioxidative properties.

[1]  W. Weglicki,et al.  Protection by beta-blocking agents against free radical-mediated sarcolemmal lipid peroxidation. , 1988, Circulation research.

[2]  N. Narita,et al.  [Quantitative flow-cytometric analysis of CD34-positive stem cells in peripheral blood stem cell harvests]. , 1994, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[3]  J. Mehta,et al.  Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol. , 1994, The American journal of cardiology.

[4]  S. Rafii,et al.  Evidence for circulating bone marrow-derived endothelial cells. , 1998, Blood.

[5]  J. Winer,et al.  Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. , 1999, Analytical biochemistry.

[6]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[7]  NoboruFukuda,et al.  Production of Angiotensin II by Homogeneous Cultures of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats , 1999 .

[8]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[9]  Pier Paolo Pandolfi,et al.  The p66shc adaptor protein controls oxidative stress response and life span in mammals , 1999, Nature.

[10]  Haruchika Masuda,et al.  Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization , 1999, Nature Medicine.

[11]  Daniel Levy,et al.  Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. , 1999, Circulation.

[12]  N. Kobayashi,et al.  Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats , 2001, Journal of hypertension.

[13]  D. Brocks,et al.  Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans. , 2001, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[14]  T. Zglinicki.  Oxidative stress shortens telomeres , 2002 .

[15]  W. Welch,et al.  A mouse model of angiotensin II slow pressor response: role of oxidative stress. , 2002, Journal of the American Society of Nephrology : JASN.

[16]  R. G. Allen,et al.  Effects of establishing cell cultures and cell culture conditions on the proliferative life span of human fibroblasts isolated from different tissues and donors of different ages. , 2002, Experimental cell research.

[17]  A. Quyyumi,et al.  Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. , 2003, The New England journal of medicine.

[18]  K. Griendling,et al.  Reactive oxygen species in the vasculature: molecular and cellular mechanisms. , 2003, Hypertension.

[19]  N. Kobayashi,et al.  Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-&kgr;B Induced by Oxidative Stress , 2003, Hypertension.

[20]  R. Brandes,et al.  Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. , 2004, Blood.

[21]  T. Sawamura,et al.  OXIDIZED LOW‐DENSITY LIPOPROTEIN INDUCES ENDOTHELIAL PROGENITOR CELL SENESCENCE, LEADING TO CELLULAR DYSFUNCTION , 2004, Clinical and experimental pharmacology & physiology.

[22]  T. Imanishi,et al.  Estrogen Reduces Angiotensin II-Induced Acceleration of Senescence in Endothelial Progenitor Cells , 2005, Hypertension Research.

[23]  T. Sawamura,et al.  Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivation , 2005, Journal of hypertension.

[24]  N. Fukuda,et al.  Oxidative stress on progenitor and stem cells in cardiovascular diseases. , 2006, Current pharmaceutical biotechnology.

[25]  M. Runge,et al.  Atherosclerosis Is Attenuated by Limiting Superoxide Generation in Both Macrophages and Vessel Wall Cells , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[26]  Koichi Matsumoto,et al.  Losartan Improves the Impaired Function of Endothelial Progenitor Cells in Hypertension via an Antioxidant Effect , 2007, Hypertension Research.

[27]  M. Tuck,et al.  Vascular Angiotensin Type 1 Receptor Expression Is Associated with Vascular Dysfunction, Oxidative Stress and Inflammation in Fructose-Fed Rats , 2007, Hypertension Research.

[28]  Koichi Matsumoto,et al.  Effects of an ARB on endothelial progenitor cell function and cardiovascular oxidation in hypertension. , 2008, American journal of hypertension.