2005 Fiscal Year Final Research Report Summary
Importance of Tall-like receptor 4 on molecular mechanisms of the oxidative stress-induced smooth muscle cell phenotypic change
| Project/Area Number |
16590691
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Yamaguchi University |
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Principal Investigator |
UMEMOTO Seiji Yamaguchi University, University Hospital, Associate Professor, 医学部附属病院, 助教授 (90263772)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Hiroki Yamaguchi University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (60322244)
YOSHIMURA Koichi Yamaguchi University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (00322248)
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| Project Period (FY) |
2004 – 2005
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| Keywords | signal trasduction / hypertension / oxidative stress / inflammation / smooth muscle cell / toll-like receptor |
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| Research Abstract |
It is reported that angiotensin II and hypertension increase vascular oxidant stress, and these factors might play an important role in vascular remodeling. To clarify the mechanisms under the smooth muscle (SM) cell phenotypic change in hypertension, we examined the effects of rennin-angiotensin system inhibitors or calcium antagonist on vascular remodeling in hypertension. Within 6 weeks, the angiotensin II type 1 (AT_1) receptor antagonist may modulate SM cell phenotype more effectively than the angiotensin-converting enzyme (ACE) inhibitor before the morphological changes occur in the spontaneously hypertensive rat (SHR)'s intramyocardial arteries through upregulation of transcription factor GATA-6. In addition, an ACE inhibitor and an AT1 receptor antagonist inhibited vascular SM cell dedifferentiation through inhibition of NAD(P)H oxidase activity and upregulation of endothelial nitric oxide (eNOS) and Akt in stroke-prone SHR aortas, suggesting that AT1 receptor-mediated NAD(P)H
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oxidase-generated reactive oxygen species, eNOS and Akt might be crucial determinants for the vascular SM cell phenotype in hypertension in vivo. In addition, dyhydropyridine calcium antagonists amlodipine may inhibit vascular remodeling and oxidative stress in the stroke-prone SHR heart by efficiently upregulating Cu/Zn superoxide dismutase (SOD), suggesting that amlodipine may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension. We further examine the effects of toll-like receptor (TLR) 4 on oxidative stress in hypertension. In control mice, both angiotensin II and norepinephrine infusion for 14 days increased systolic blood pressure from 100 mm Hg to 160 mm Hg. Norepinephrine caused a significant increase in superoxide content in the aorta, whereas this was completely abolished in TLR4 deficient mice, indicating that TLR4 might play an important role in the angiotensin II-induced oxidative stress in the aorta in hypertension. Less
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