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Chymase inhibition improves vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats

Takai, Shinjia; Jin, Denana; Chen, Hongb; Li, Wenc; Yamamoto, Hideyukic; Yamanishi, Kyosukec; Miyazaki, Mizuoa; Higashino, Hideakid; Yamanishi, Hiromichid; Okamura, Harukic

doi: 10.1097/HJH.0000000000000231
ORIGINAL PAPERS: Pathophysiological aspects

Objective: To clarify the role of chymase in hypertension, we evaluated the effect of a chymase inhibitor, TY-51469, on vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats (SHR-SP).

Methods: SHR-SP were treated with TY-51469 (1 mg/kg per day) or placebo from 4 to 12 weeks old or until death. Wistar–Kyoto rats were used as a normal group.

Results: SBP was significantly higher in both the placebo and TY-51469 groups than in the normal group, but there was no significant difference between the two treatment groups. Plasma renin, angiotensin-converting enzyme activity and angiotensin II levels were not different between the placebo and TY-51469 groups. In contrast, vascular chymase-like activity was significantly higher in the placebo than in the normal group, but it was reduced by TY-51469. Acetylcholine-induced vascular relaxation was significantly higher in the TY-51469 group than in the placebo group. There was significant augmentation of the number of monocytes/macrophages and matrix metalloproteinase-9 activity in aortic tissue from the placebo group compared with the normal group, and these changes were attenuated by TY-51469. There were also significant increases in mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the placebo group that were attenuated by TY-51469. Cumulative survival was significantly prolonged in the TY-51469 group compared with the placebo group.

Conclusion: Chymase might play an important role in vascular dysfunction via augmentation both of matrix metalloproteinase-9 activity and monocyte/macrophage accumulation in SHR-SP, and its inhibition may be useful for preventing vascular remodeling and prolonging survival.

aDepartment of Pharmacology, Osaka Medical College, Osaka, Japan

bDepartment of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

cLaboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo

dHirakata Ryoikuen, Osaka, Japan

Correspondence to Shinji Takai, PhD, Department of Pharmacology, Osaka Medical College, Osaka 569-8686, Japan. Tel: +81 72 684 7292; fax: +81 72 684 6518; e-mail:

Abbreviations: ACE, angiotensin-converting enzyme; MCP, monocyte chemoattractant protein; MDA, malondialdehyde; MMP, matrix metalloproteinase; PRA, plasma renin activity; ROS, reactive oxidative stress; RT-PCR, real-time PCR; SHR-SP, spontaneously hypertensive rats; TNF, tumor necrosis factor; WKY, Wistar–Kyoto

Received 16 January, 2014

Revised 28 March, 2014

Accepted 28 March, 2014

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