Apolipoprotein B of low-density lipoprotein impairs nitric oxide-mediated endothelium-dependent relaxation in rat mesenteric arteries.
Apolipoprotein B (ApoB) of low-density lipoprotein (LDL) causes endothelial dysfunction in the initial stage of atherogenesis. The present study was designed to explore the underlying molecular mechanisms involved. Rat mesenteric arteries were organ cultured in the presence of different concentrations of ApoB or LDL. Vasodilation induced by acetylcholine was monitored by a sensitive myograph. Nitric oxide (NO), endothelium-dependent hyperpolarizing factor (EDHF) and prostacyclin (PGI2) pathways were characterized by using specific pathway inhibitors. Real-time PCR and immunohistochemistry with confocal microscopy were used to examine alteration of mRNA and protein expressions for NO synthases (eNOS and iNOS) and cycloxygenase (COX), respectively. Lipid peroxidation was measured by thiobarbituric acid reactive substances. In the presence of either LDL or ApoB for 24h concentration-dependently attenuated the endothelium-dependent vasodilation. Immunohistochemistry staining of endothelial cell marker CD31 was weaker in the presence of LDL, indicating that LDL induced damage to the endothelium. Using the pathway specific inhibitors demonstrated that LDL-induced impairing vasodilation was mainly due to attenuation of NO pathway. This was supported by decreasing mRNA (real-time PCR) and protein expression (immunohistochemistry) for eNOS and iNOS, but not COX, in the presence of LDL. In addition, the levels of lipid peroxidation significantly increased in the presence of LDL for 24h. In conclusion, ApoB of LDL impairs vasodilation with damaging the endothelium and attenuating the NO-mediated endothelium-dependent relaxation, which might associate with lipid peroxidation and contribute to the development of cardiovascular disease.
Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, China; Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, SE-221 84 Lund, Sweden.
Yaping
Y
Zhang
Xiamen Diabetes Institute, the First Affiliated Hospital of Xiamen University, Xiamen, China.
Wei
W
Zhang
Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, SE-221 84 Lund, Sweden.
Lars
L
Edvinsson
Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, China; Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, SE-221 84 Lund, Sweden. Electronic address: cangbaoxu@yahoo.com.
Cang-Bao
CB
Xu
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001055:Apolipoproteins B / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
D001055:Apolipoproteins B; D001685:Biological Factors; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine
5-hydroxytryptamine (PubChem CID: 5202); Acetylcholine (PubChem CID: 187); Apolipoprotein B; Cardiovascular disease; Endothelial dysfunction; Lipid peroxidation; Low-density lipoprotein; N(ω)-nitro-l-arginine methyl ester (PubChem CID: 39836); Vasodilation; apamin (PubChem CID: 16129677); charybdotoxin (PubChem CID: 56842037); indomethacin (PubChem CID: 3715)