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PRECLINICAL STUDY

Angiotensin Receptor-1 Blocker Inhibits Atherosclerotic Changes and Endothelial Disruption of the Aortic Valve in Hypercholesterolemic Rabbits

Kumiko Arishiro, MD^_*, Masaaki Hoshiga, MD, PhD^_*,_*, Nobuyuki Negoro, MD, PhD^_*, Denan Jin, MD, PhD, Shinji Takai, PhD, Mizuo Miyazaki, MD, PhD, Tadashi Ishihara, MD, PhD^_* and Toshiaki Hanafusa, MD, PhD^_*

^_* First Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
Department of Pharmacology, Osaka Medical College, Takatsuki, Osaka, Japan.

Manuscript received August 23, 2006; revised manuscript received November 1, 2006, accepted November 23, 2006.

^_* Reprint requests and correspondence: Dr. Masaaki Hoshiga, First Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. (Email: in1026{at}poh.osaka-med.ac.jp).

This work was partly presented at the 55th Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 11 to 14, 2006, and published in abstract form (J Am Coll Cardiol 2006;47 Suppl A:284A).

Objectives: We sought to examine the effect of angiotensin receptor blocker (ARB) on the formation of lesions in the aortic valves of hypercholesterolemic rabbits.

Background: Recently, atherosclerosis has been recognized as a mechanism that is responsible for calcific aortic stenosis. The effect of ARBs might help to prevent aortic stenosis because they have multiple antiatherosclerotic effects.

Methods: Male Japanese white rabbits (n = 36) were separated as follows: control with chow diet (C) and vehicle (V) groups, both of which were fed a 1% cholesterol diet for 8 weeks, and an ARB group (A), which was fed a 1% cholesterol diet for 8 weeks with ARB (olmesartan, 1 mg/kg/day) for the last 4 weeks.

Results: This dose of olmesartan did not affect either blood pressure or cholesterol levels. Dietary cholesterol induced fatty deposition with macrophage accumulation and osteopontin coexpression in valve leaflets, whereas ARB decreased macrophage accumulation (% area: V, 9.3 ± 0.34; A, 1.4 ± 0.30; p = 0.003) and osteopontin expression (p = 0.017). Angiotensin-converting enzyme was also up-regulated in V and decreased by olmesartan (p = 0.015). Immunohistochemistry with anti-CD31 antibody revealed that dietary cholesterol disrupted and olmesartan preserved endothelial integrity on the lesion-prone aortic side of the valve (% CD31-positive circumference: V, 30 ± 3.7; A, 62 ± 4.8; p = 0.003). Numbers of alpha-smooth muscle actin-positive myofibroblasts were increased in V and decreased by olmesartan (p = 0.003). Real-time polymerase chain reaction revealed that increased amounts of messenger ribonucleic acid for osteoblast-specific transcription factor core binding factor alpha-1 in V were diminished by olmesartan.

Conclusions: Atherosclerotic changes in the aortic valves of rabbits fed with cholesterol were inhibited by ARB, whereas endo-thelial integrity was preserved and transdifferentiation into myofibroblasts and/or osteoblasts in valve leaflets was inhibited.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ARB = angiotensin receptor blocker   AS = aortic stenosis   Cbfa-1 = core binding factor alpha-1   DNA = deoxyribonucleic acid   eNOS = endothelial nitric oxide synthase   RNA = ribonucleic acid   RT-PCR = reverse transcriptional-polymerase chain reaction   TGF = transforming growth factor