Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta.
OBJECTIVE
The role of chymase (a mast cell-derived angiotensin II-forming serine proteinase) in aortic lipid deposition was investigated using an orally active, non-peptide chymase inhibitor, SUN-C8257.


METHODS
Male golden Syrian hamsters, 8 weeks old, were fed with a standard rodent meal supplemented with or without 0.5% cholesterol and 10% coconut oil for 12 weeks. The hamsters fed high cholesterol diet were further separated into two groups treated with or without SUN-C8257 for 12 weeks. The aortic lipid deposition was visualized by Oil red O staining and planimetrically measured. Immunohistochemical staining for angiotensin II (Ang II) of the aortic root region was performed. Aortic Ang II-forming activity was measured using Ang I as a substrate. Plasma total-, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol and triglyceride were quantified by enzymatic methods. Plasma Ang I and Ang II were measured by radioimmunoassay.


RESULTS
After 12 weeks of high cholesterol diet, aortic chymase activity in the untreated group increased significantly and showed a positive correlation with plasma total- and LDL-cholesterol. This group of hamsters developed marked lipid deposits in the aortic intima. However, treatment with SUN-C8257 significantly suppressed aortic lipid deposition without changing body weight, blood pressure, plasma LDL-cholesterol and Ang II levels. The level of the adventitial Ang II-immunoreactivity was markedly inhibited in the group treated with SUN-C8257.


CONCLUSIONS
Our results suggest that arterial chymase may participate in the acceleration of lipid deposition in arterial walls exposed to high plasma cholesterol and that inhibition of arterial chymase may retard the progression of atherosclerosis.
Uehara
Yoshinari
Y
Department of Internal Medicine, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Urata
Hidenori
H
Ideishi
Munehito
M
Arakawa
Kikuo
K
Saku
Keijiro
K
D000704:Analysis of Variance; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001011:Aorta; D002784:Cholesterol / Q000032:analysis / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D053818:Chymases; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000378:metabolism*
D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011799:Quinazolines; D012333:RNA, Messenger; C466919:SUN-C 8257; D015842:Serine Proteinase Inhibitors; D014280:Triglycerides; D000804:Angiotensin II; D000803:Angiotensin I; D002784:Cholesterol; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases