Polymorphonuclear leukocytes may impair endothelial function: results of crossover randomized study of lipid-lowering therapies.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Sugano
Ryo
R
Department of Internal Medicine III and The Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
Matsuoka
Hidehiro
H
Haramaki
Nobuya
N
Umei
Hidekazu
H
Murase
Eiko
E
Fukami
Kei
K
Iida
Shuji
S
Ikeda
Hisao
H
Imaizumi
Tsutomu
T
D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D008078:Cholesterol, LDL / Q000097:blood; D018592:Cross-Over Studies; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004811:Epichlorohydrin / Q000008:administration & dosage; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000276:immunology*; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D012117:Resins, Synthetic / Q000008:administration & dosage; D012694:Serine / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D007093:Imidazoles; D007211:Indoles; D008077:Lipoproteins, LDL; D012117:Resins, Synthetic; C417427:colestimide; C099252:oxidized low density lipoprotein; D004811:Epichlorohydrin; D013481:Superoxides; D012694:Serine; D000077340:Fluvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III