Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells.
The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by approximately 30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker.
Ohtani
Kisho
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Egashira
Kensuke
K
Ihara
Yoshiko
Y
Nakano
Kaku
K
Funakoshi
Kouta
K
Zhao
Gang
G
Sata
Masataka
M
Sunagawa
Kenji
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D003251:Constriction, Pathologic; D007083:Iliac Artery; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008252:Macaca fascicularis; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits; D012008:Recurrence; D012084:Renin-Angiotensin System; D013234:Stem Cells / Q000473:pathology*; D015607:Stents / Q000009:adverse effects*; D013777:Tetrazoles / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D007093:Imidazoles; D018836:Inflammation Mediators; D007527:Isoenzymes; D013777:Tetrazoles; D000068756:Valsartan; C437965:olmesartan; D019255:NADPH Oxidases; D014633:Valine