| Project/Area Number |
15590735
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Mie University |
|---|
Principal Investigator |
IMANAKA Kyoko Mie University, Faculty of Medicine, Professor, 医学部, 講師 (00242967)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YOSHIDA Toshimichi Mie University, Faculty of Medicine, Professor, 医学部, 教授 (80166959)
ONISHI Katusya Mie University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (40343222)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
|
|---|
| Keywords | Hypertension / Heart / fibrosis / Angiotensin / Extracellular Matrix / Tenascin / Mouse / アンジオテンシン |
|---|
| Research Abstract |
Cardiac fibrosis is often associated with hypertensive hearts or diabetic heart, which affects cardiac function. However, its molecular mechanism still remains unclear. Fibrotic lesions are formed through multiple steps of synthesis of various extracellular matrix(ECM) molecules. Tenascin-C(TN-C) is one of the acute stage proteins of the cascade. To elucidate the mechanisms of myocardial fibrosis in hypertensive heart, we treated BALB/c mice with angiotensin II(Ang II). Ang II treatment elevated blood pressure and histological examination of the heart evidenced increase of collagen fibers at perivascular area accompanied with accumulation of macrophages and deposition of TN-C. Marked upregulation of TN-C mRNA expression was detected by quantitative RT-PCR, while collagen I and III mRNA also tended to increase. In situ hybridization demonstrated that interstitial fibroblasts at perivascular area synthesized TN-C. The fibrotic In TN-C knockout mice, An aldosterone receptor antagonist, eplerenone(Ep), significantly reduced fibrosis, macrophage accumulation and expression of TN-C, despite similar levels of hypertension. Next, we examined the regulatory mechanism using culture cells. Ang II stimulated cultured cardiac fibroblasts to express TN-C, while aldosterone did not. Neither aldosterone nor Ep affected the induction of TN-C by Ang II. These results suggest that, during progression of Ang II-induced cardiac fibrosis, aldosterone could play a crucial role by mediating inflammation at perivascular region, which indirectly induces expression of TN-C, a regulator of the initial step of fibrosis.
|
