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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1262.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Polymorphonuclear Leukocytes May Impair Endothelial Function

Results of Crossover Randomized Study of Lipid-Lowering Therapies

Ryo Sugano; Hidehiro Matsuoka; Nobuya Haramaki; Hidekazu Umei; Eiko Murase; Kei Fukami; Shuji Iida; Hisao Ikeda; Tsutomu Imaizumi

From the Department of Internal Medicine III and The Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.

Correspondence to Hidehiro Matsuoka, MD, PhD, FAHA, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan. E-mail matsuoka{at}med.kurume-u.ac.jp

Objectives— To examine whether polymorphonuclear leukocytes (PMNs) in hypercholesterolemia (HC) are activated to generate large amount of superoxide in vivo and hence impair endothelial function and, if so, whether statins, which possess anti-inflammatory properties, may restore PMN-mediated endothelial dysfunction.

Methods and Results— At baseline, subjects with HC showed impaired endothelial function (P<0.001), estimated by flow-mediated vasodilation of the brachial artery, and increased susceptibility of low-density lipoprotein (LDL) to oxidation (P<0.0001) compared with control subjects. PMNs obtained from HC produced greater amount of superoxide (P<0.0001), showed higher adhesiveness to cultured endothelial cells (HUVECs) (P<0.0001), and impaired endothelial nitric oxide synthase (eNOS) Ser¹¹⁷⁷ phosphorylation of HUVECs compared with controls (P<0.001). Crossover administration of fluvastatin or colestimide for 3 months lowered LDL to the same levels (P<0.001 for both). Endothelial function was restored (P<0.0001). LDL oxidation (P<0.0001) and superoxide release from PMNs (P<0.0001) were diminished only in fluvastatin but not in colestimide arm. Fluvastatin attenuated PMN adhesion to HUVECs (P<0.0001) and restored eNOS Ser¹¹⁷⁷ phosphorylation of HUVECs (P<0.001).

Conclusion— Statins may improve endothelial function at least in part by inactivating neutrophils independently of LDL reduction. Our results raise a novel concept that polymorphonuclear leukocytes may attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis.

Fluvastatin but not colestimide restored endothelium-dependent vasodilation and diminished LDL oxidation and leukocyte activity. PMNs from hypercholesterolemia showed greater cell adhesion and impaired eNOS phosphorylation, which were normalized by fluvastatin. These findings suggest that fluvastatin may improve endothelial function by its anti-inflammatory properties against PMNs, independently of LDL reduction.

Key Words: atherosclerosis • hypercholesterolemia • inflammation • oxidative stress • polymorphonuclear leukocytes

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