Losartan improves the impaired function of endothelial progenitor cells in hypertension via an antioxidant effect.
We evaluated the effects of the angiotensin II (Ang II) receptor blocker (ARB) losartan on the formation and number of endothelial progenitor cells (EPCs) in hypertensive rats. Wistar-Kyoto (WKY) rats and stroke-prone, spontaneously hypertensive rats (SHR-SP) were salt-loaded and then treated with losartan (10 mg/kg/day), trichlormethiazide (TCM; 1.6 mg/kg/day), or tempol (1 mmol/L) for 2 weeks. Peripheral blood mononuclear cells were isolated, subjected to flow cytometric analysis to determine the number of circulating EPCs, cultured to assay EPC colony formation, and subjected to a migration chamber assay to evaluate EPC migration. Oxidative stress in EPCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay. The results showed that the number, colony formation, and migration of EPCs were markedly decreased in SHR-SP compared to those in WKY rats. The TBARS scores were significantly greater in SHR-SP than in WKY rats. Losartan and TCM decreased systolic blood pressure in SHR-SP to similar levels. Losartan and tempol increased the number of circulating EPCs and colony formation, and inhibited oxidation in SHR-SP. TCM did not affect the EPC number, colony formation, or oxidation. Both losartan and TCM stimulated EPC migration. Expression of gp91(phox), p22(phox), and p47(phox) mRNA in tissues was significantly decreased by losartan but not by TCM. These results indicate that the formation and function of EPCs are impaired by oxidative stress in SHR-SP. This is the first report to show that losartan improves the proliferation and function of EPCs in hypertension, suggesting that ARBs are useful to repair hypertensive vascular injuries.
Yao
En-Hui
EH
Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Matsumoto
Taro
T
Kobayashi
Naohiko
N
Katakawa
Mayumi
M
Yamamoto
Chii
C
Tsunemi
Akiko
A
Suzuki
Ryo
R
Ueno
Takahiro
T
Matsumoto
Koichi
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013113:Spin Labels; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D003497:Cyclic N-Oxides; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D019255:NADPH Oxidases; D019808:Losartan; C001803:tempol