Journal of Nippon Medical School: Vol.67 No.5 page.342

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ArticleTitle Expression of Endothelin-1 After Endothelial Denudation of Thoracic Aortas in Experimental Hypercholesterolemic Rats

AuthorList Tomonaga Yoshida¹, Kaname Kiuchi¹, Jun Nejima¹, Mitsuhiro Kudo², Goro Asano² and Teruo Takano¹

Affiliation ¹First Department of Internal Medicine and ²Department of Pathology, Nippon Medical School

Language EN

Volume 67

Issue 5

Year 2000

Page 342-351

Received May 23, 2000

Accepted June 26, 2000

Keywords prepro endothelin-1 mRNA, hypercholesterolemia, neointima formation, angioplasty, restenosis

Abstract Although endothelin-1 (ET-1) is involved in balloon-induced neointima formation, the role of ET-1 in balloon-induced neointima formation in hypercholesterolemia is unclear. In addition, it remains to be determined whether ET-1 is produced by endothelial cells or vascular smooth muscle cells, or both. We investigated tissue immunoreactive ET-1 levels by immunoblot analysis, localization of ET-1 immunoreactivity by immunohistochemistry, and expression of preproET-1 mRNA by in situ hybridization in balloon-induced neointima formation in experimental hypercholesterolemic rats. Serum total cholesterol levels were significantly higher (p< 0.01) in the 5%cholesterol-diet group (194± 17 mg/dl, n=20) than in the normal-diet group (64± 2 mg/dl, n=20). Before and after endothelial denudation, plasma ET-1 levels and tissue immunoreactive ET-1 levels were significantly higher in cholesterol-diet rats. The expression of preproET-1 mRNA by in situ hybridization was observed in the nuclei of endothelial cells, but not medial smooth muscle cells in normal- or cholesterol diet rats. After endothelial denudation, plasma ET-1 levels and serum total cholesterol levels did not change in either the normal- or the cholesterol-diet rats. Tissue level of ET-1 tended to increase at 3 days after denudation in normal-diet rats (1.0± 0.1 vs 2.6± 0.2 density ratio, p< 0.05), although endothelial cells had not yet regenerated. The expression of preproET-1 mRNA by in situ hybridization was not observed at 3 days after endothelial denudation in either endothelial or medial smooth muscle cells in normal-diet rats. Four weeks after denudation, regeneration of endothelial cells was almost complete, and an intimal hyperplasia was observed. Tissue ET-1 levels were significantly elevated 4 weeks after endothelial denudation in normal-diet rats (1.0± 0.1 vs 7.6± 0.2 density ratio, p< 0.05). The expression of preproET-1 mRNA by in situ hybridization was observed in the nuclei of regenerated endothelial cells after endothelial denudation, and in smooth muscle cells migrating into the intima, but was not observed in medial smooth muscle cells in normal-diet rats. A similar pattern was observed in cholesterol-diet rats. We concluded that ET-1 was involved in neointima formation and that ET-1 was produced by both endothelial and neointimal smooth muscle cells, but not medial smooth muscle cells after endothelial denudation in experimental hypercholesterolemic rats.

Correspondence to Kaname Kiuchi, M. D, First Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan

ArticleTitle	Expression of Endothelin-1 After Endothelial Denudation of Thoracic Aortas in Experimental Hypercholesterolemic Rats
AuthorList	Tomonaga Yoshida¹, Kaname Kiuchi¹, Jun Nejima¹, Mitsuhiro Kudo², Goro Asano² and Teruo Takano¹
Affiliation	¹First Department of Internal Medicine and ²Department of Pathology, Nippon Medical School
Language	EN
Volume	67
Issue	5
Year	2000
Page	342-351
Received	May 23, 2000
Accepted	June 26, 2000
Keywords	prepro endothelin-1 mRNA, hypercholesterolemia, neointima formation, angioplasty, restenosis
Abstract	Although endothelin-1 (ET-1) is involved in balloon-induced neointima formation, the role of ET-1 in balloon-induced neointima formation in hypercholesterolemia is unclear. In addition, it remains to be determined whether ET-1 is produced by endothelial cells or vascular smooth muscle cells, or both. We investigated tissue immunoreactive ET-1 levels by immunoblot analysis, localization of ET-1 immunoreactivity by immunohistochemistry, and expression of preproET-1 mRNA by in situ hybridization in balloon-induced neointima formation in experimental hypercholesterolemic rats. Serum total cholesterol levels were significantly higher (p< 0.01) in the 5%cholesterol-diet group (194± 17 mg/dl, n=20) than in the normal-diet group (64± 2 mg/dl, n=20). Before and after endothelial denudation, plasma ET-1 levels and tissue immunoreactive ET-1 levels were significantly higher in cholesterol-diet rats. The expression of preproET-1 mRNA by in situ hybridization was observed in the nuclei of endothelial cells, but not medial smooth muscle cells in normal- or cholesterol diet rats. After endothelial denudation, plasma ET-1 levels and serum total cholesterol levels did not change in either the normal- or the cholesterol-diet rats. Tissue level of ET-1 tended to increase at 3 days after denudation in normal-diet rats (1.0± 0.1 vs 2.6± 0.2 density ratio, p< 0.05), although endothelial cells had not yet regenerated. The expression of preproET-1 mRNA by in situ hybridization was not observed at 3 days after endothelial denudation in either endothelial or medial smooth muscle cells in normal-diet rats. Four weeks after denudation, regeneration of endothelial cells was almost complete, and an intimal hyperplasia was observed. Tissue ET-1 levels were significantly elevated 4 weeks after endothelial denudation in normal-diet rats (1.0± 0.1 vs 7.6± 0.2 density ratio, p< 0.05). The expression of preproET-1 mRNA by in situ hybridization was observed in the nuclei of regenerated endothelial cells after endothelial denudation, and in smooth muscle cells migrating into the intima, but was not observed in medial smooth muscle cells in normal-diet rats. A similar pattern was observed in cholesterol-diet rats. We concluded that ET-1 was involved in neointima formation and that ET-1 was produced by both endothelial and neointimal smooth muscle cells, but not medial smooth muscle cells after endothelial denudation in experimental hypercholesterolemic rats.
Correspondence to	Kaname Kiuchi, M. D, First Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan