title: Contribution of the WHHL rabbit, an animal model of familial hypercholesterolemia, to elucidation of the anti-atherosclerotic effects of statins.
abstract: This year marks the 40th year since the discovery of a mutant rabbit showing spontaneous hyperlipidemia, which is the proband of the Watanabe heritable hyperlipidemic (WHHL) rabbit strain, an animal model of familial hypercholesterolemia, and the first statin, a general term for inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, a rate limiting enzyme in cholesterol biosynthesis. Nowadays, statins are the primary drug of choice for treating cardiovascular disease. Although several reviews have described clinical trials and in vitro studies of statins, the anti-atherosclerotic effects of statins on animal models have not been comprehensively reviewed. This review summarized the contribution of WHHL rabbits to elucidating the anti-atherosclerotic effects of statins in vivo. Studies using WHHL rabbits verified that statins suppress plaque destabilization by reducing unstable components (foam cells derived from macrophages, foam cell debris, and extracellular lipid accumulation), preventing smooth muscle cell reductions, and increasing the collagen content of plaques. In addition, the expression of matrix metalloproteinases and tissue factor are decreased in intimal macrophages by statin treatment. Lipid-lowering effects of statins alter plaque biology by reducing the proliferation and activation of macrophages, a prominent source of the molecules responsible for plaque instability and thrombogenicity. Although statins remain the standard treatment for cardiovascular disease, new therapeutics are eagerly awaited. WHHL rabbits will continue to contribute to the development of therapeutics.
authors.affiliation: Institute for Experimental Animals, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Division of Comparative Pathophysiology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: ieakusm@med.kobe-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Tomonari
authors.initials: T
authors.lastname: Koike
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy*; D002784:Cholesterol / Q000096:biosynthesis; D004195:Disease Models, Animal; D005487:Foam Cells / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy*; D006938:Hyperlipoproteinemia Type II; D008264:Macrophages / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000188:drug therapy; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol
keywords: Anti-atherosclerotic effects; Coronary atherosclerosis; Hypolipidemic effects; Plaque stabilization; Species differences; Statin; WHHL rabbit