Effects of an ARB on endothelial progenitor cell function and cardiovascular oxidation in hypertension.
BACKGROUND
Angiotensin II (Ang II) receptor blocker (ARB) has been reported to have protective effects on the cardiovascular system independent of blood pressure reduction. Endothelial progenitor cells (EPCs) play a significant role in neovascularization of ischemic tissue. The average lifespan of EPCs was recently reported to be shortened by oxidative stress and regulated by anti-oxidative mechanisms. It has been reported that EPCs are present in peripheral blood and have the ability to repair cardiovascular damage. We investigated the effects of an ARB, candesartan, on EPC function and cardiovascular oxidation in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHR-SP) in vivo.


METHODS
Salt-loaded SHR-SP were treated with candesartan (1 mg/kg/day), a diuretic (trichlormethiazide, TCM, 1.6 mg/kg/day), or an antioxidant (tempol, 5 mg/kg/day) for 2 weeks. Peripheral blood mononuclear cells (MNCs) were isolated and cultured to assay EPC colony formation and migration. Oxidative stress in EPCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay. We evaluated messenger RNA (mRNA) expression of c-kit in the heart, the renin-angiotensin system (RAS) in EPC colonies, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit in cardiovascular organs.


RESULTS
Candesartan and tempol, but not TCM, markedly increased EPC colony number in SHR-SP and reduced TBARS. Candesartan also significantly decreased mRNA expression of NADPH oxidase subunits in cardiovascular organs and increased cardiac c-kit mRNA expression. EPCs expressed mRNAs of renin, cathepsin D, chymase, and Ang II type 1 and type 2 receptors.


CONCLUSIONS
Candesartan, an ARB, improves EPC dysfunction and increases cardiac c-kit expression through the anti-oxidative mechanism in hypertension. The local RAS induces oxidative stress and regulates the EPC functions.
Yu
Yi
Y
Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Yao
En-Hui
EH
Matsumoto
Taro
T
Kobayashi
Naohiko
N
Suzuki
Ryo
R
Tahira
Yoshiko
Y
Ueno
Takahiro
T
Matsumoto
Koichi
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013113:Spin Labels; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014237:Trichlormethiazide / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D054377:Chemokine CXCL12; D003497:Cyclic N-Oxides; D004232:Diuretics; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D013777:Tetrazoles; D017392:Thiobarbituric Acid Reactive Substances; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D019255:NADPH Oxidases; D019009:Proto-Oncogene Proteins c-kit; D014237:Trichlormethiazide; C081643:candesartan; C001803:tempol