title: Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function.
abstract: Several studies have suggested that hypertriglyceridemia is a common risk factor for coronary heart disease. Although increasing serum levels of triglyceride correlate with hypercoagulability, little is known about the contribution of hypertriglyceridemia to vascular function. We successfully segregated two lines of rabbits with genetically-determined severely high (TGH; 2764 +/- 413 mg/dl) and moderately high (TGL; 191 +/- 12 mg/dl) levels of triglyceride, but with comparable levels of total cholesterol, from Watanabe heritable hyperlipidemic rabbits. To determine whether hypertriglyceridemia was involved in alterations of vascular function, we conducted isometric tension studies and analyzed protein expression on thoracic aortic rings isolated from young (3-4 month) TGH, TGL and Japanese White rabbit (JW). No difference in percentage of plaque area in the thoracic aorta was found between TGH and TGL. Relaxing responses, evoked by sodium nitroprusside were similar in JW, TGL and TGH, but endothelium-dependent relaxation to acetylcholine was impaired in TGH compared with JW or TGL (maximal relaxation in JW; 83.5 +/- 2.7%, TGL; 79.9 +/- 5.3%, TGH; 59.1 +/- 5.7%, p<0.05). Relaxation to A23187 was also attenuated in TGH compared with JW, but not significantly different between TGL and JW. Endothelium-independent relaxation elicited by isoproterenol in TGH was significantly decreased compared with JW or TGL (maximal relaxation in JW; 95.2 +/- 2.6% TGL; 91.0 +/- 4.9%, TGH; 75.1 +/- 5.2%, p<0.05). Protein expression of angiotensin II type-1 receptor was increased in TGH and that of nitric oxide synthases-3 was attenuated in TGH compared with TGL. This is the first study showing that endothelium-dependent and -independent vascular relaxation under the condition of combined hyperlipidemia was severely impaired as compared to that under only hypercholesterolemia. These results suggest that hypertriglyceridemia aggravates functional impairment induced by hypercholesterolemia in endothelial and smooth muscle cells.
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. tshishid@med.id.yamagata-u.ac.jp
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Katsunari
authors.initials: K
authors.lastname: Tasaki
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takasaki
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Itoh
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
authors.forename: Tsunekata
authors.initials: T
authors.lastname: Ito
authors.forename: Yumi
authors.initials: Y
authors.lastname: Katano
authors.forename: Ichiro
authors.initials: I
authors.lastname: Wakabayashi
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000033:anatomy & histology / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D004730:Endothelium, Vascular / Q000033:anatomy & histology* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D014280:Triglycerides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007476:Ionophores; D014280:Triglycerides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000001:Calcimycin; D002784:Cholesterol; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005947:Glucose