2006 Fiscal Year Final Research Report Summary
Inverse agonist activity of angiotensin II type 1 receptor blockers
| Project/Area Number |
17590766
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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 | Kanazawa Medical University |
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Principal Investigator |
AKAZAWA Sumiyo Kanazawa Medical University, The 21^<st> Century Multidisciplinary Medical Center・Lifestyle-related Disease Center, Research Associate, 大学病院, 助手 (80340016)
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| Co-Investigator(Kenkyū-buntansha) |
KOMURO Issei Chiba University, Graduate School of Medicne, Department of Cardiovascular Science and Medicine, Professor, 大学院医学研究院, 教授 (30260483)
KAJINAMI Kouji Kanazawa Medical University, Department of Cardiology, Professor, 医学部, 教授 (40262563)
OKUBO Shinji Tokyo Medical University, Kasumigaura Hospital, Professor, 医学部, 教授 (50213658)
AKAZAWA Hiroshi Chiba University, Graduate School of Medicne, Division of Cardiovascular Pathophysiology, Research Associate, 大学院医学研究院, 助手相当 (20396683)
TAKEDA Kenji Kanazawa Medical University, Department of Cardiology, Research Associate, 医学部, 助手 (90340009)
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| Project Period (FY) |
2005 – 2006
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| Keywords | cardiomyocyte / inverse agonist / mechanical stress / cardiac hypertrophy / angiotensin II / ARB / heart failure / ERK |
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| Research Abstract |
The angiotensin II (AngII) type 1 (AT_1) receptor is a G protein-coupled receptor that plays a crucial role in the development of load-induced cardiac hypertrophy. We previously reported that mechanical stress can induce hypertrophic responses by activating AT_1 receptor independently of AngII, and that this activation can be inhibited by an AT_1 receptor blocker (ARB) with inverse agonist activity. In this study, we searched for the critical region of the AT_1 receptor, which is responsible for mechanical stretch-induced activation. In addition, we compared the inverse agonist activity in 4 kinds of hydrophilic ARBs, which share the bi-phenyl-tetrazole ring structure in common, and examined the relationship between the chemical structure and the inverse agonist activity in ARBs.
We first constructed a series of chimera receptors consisting of the AT_1 receptor and the endothelin-1 type A receptor, which is a G protein-coupled receptor without responsiveness to mechanical stress. Examin
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ation of ERKs activation in chimera receptors revealed that a region ranging from Lys199 to Ser252 was critical for AngII-induced receptor activation. However, the same approach failed to identify the region that is critical for mechanical stress-induced receptor activation. We suppose that disulfide bonds might be aberrantly formed in chimera receptors, and that mechanical stress might induce undefined conformational change of chimera receptors.
Losartan showed mild inverse agonist activity, while valsartan, candesartan, and olmesartan showed moderate to exceeding inverse agonist activities, when the inhibitory effects either on constitutive activity of the AT_1-N111G mutant receptor or on mechanical stress-induced activation of the AT_1 receptor were examined. The presence of the carboxyl group at the imidazole ring in the potent inverse agonists suggested that the chemical structure plays an important role in exhibiting the potent inverse agonist activity. Further analysis of structure-function of the AT_1 receptor and investigation of the relationship between the chemical structure and the inverse agonist activity in ARBs will be of help for the establishment of an ideal ARB with more potent inverse agonist activity and more protective effect against the organ damages. Less
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