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1.
Eur J Pharmacol ; 551(1-3): 92-7, 2006 Dec 03.
Article in English | MEDLINE | ID: mdl-17045583

ABSTRACT

The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.


Subject(s)
Endothelium, Vascular/drug effects , Folic Acid/pharmacology , Hyperhomocysteinemia/physiopathology , Mesenteric Arteries/drug effects , Vasodilation/drug effects , Animals , Clotrimazole/pharmacology , Cystathionine beta-Synthase/deficiency , Cystathionine beta-Synthase/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelium, Vascular/physiopathology , Enzyme Inhibitors/pharmacology , Folic Acid/blood , Homocysteine/blood , Hyperhomocysteinemia/blood , Mesenteric Arteries/physiopathology , Methacholine Chloride/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitroprusside/pharmacology , Vasodilator Agents/pharmacology
2.
Arterioscler Thromb Vasc Biol ; 26(4): 851-6, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16410454

ABSTRACT

OBJECTIVE: Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization. METHODS AND RESULTS: Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques. CONCLUSIONS: These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.


Subject(s)
Apolipoproteins E , Atherosclerosis/pathology , Cathepsins , Animals , Apolipoproteins E/deficiency , Atherosclerosis/genetics , Brachiocephalic Trunk/pathology , Cathepsins/deficiency , Cathepsins/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Rupture, Spontaneous/genetics , Rupture, Spontaneous/pathology
3.
Metabolism ; 53(6): 760-5, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15164325

ABSTRACT

Increased total plasma homocysteine is an independent risk factor for cardiovascular disease. This study was designed to determine whether it can impair endothelial function, by examining the recovery of acetylcholine-evoked relaxation following mechanical denudation of the endothelium in the arteries of cystathionine beta-synthase knockout (CbetaS(+/-)) mice. Heterozygous CbetaS(+/-) mice had total plasma homocysteine concentrations significantly higher (8.9 +/- 1.1 micromol/L, n = 12) than strain-matched wild-types (4.6 +/- 0.4 micromol/L, n = 5; P =.003). Left common carotid arteries were denuded of endothelium using a 250-microm polytetrafluoroethylene filament. After 10 days, when the endothelium had completely regrown, relaxation to acetylcholine was measured in precontracted segments of artery. Uninjured right carotid arteries from the same animals served as internal controls. Relaxation to acetylcholine was significantly attenuated in the injured arteries of the CbetaS(+/-) mice, compared to wild-types (P =.017); furthermore, there was a significant negative correlation between sensitivity to acetylcholine and total plasma homocysteine concentration measured in the same animal (r = -0.69, P <.003). These data suggest that even modest homocysteinemia has a deleterious effect on the function of healed endothelium in mouse arteries. This may account for its adverse influence on chronic cardiovascular disease.


Subject(s)
Endothelium, Vascular/physiology , Homocysteine/blood , Acetylcholine/pharmacology , Animals , Carotid Artery Injuries/metabolism , Carotid Artery Injuries/pathology , Carotid Artery, Common/drug effects , Carotid Artery, Common/metabolism , Carotid Artery, Common/pathology , Carotid Artery, Common/ultrastructure , Cystathionine beta-Synthase/genetics , Dose-Response Relationship, Drug , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth, Vascular/drug effects , Recovery of Function , Vasodilation/drug effects , Vasodilator Agents/pharmacology
4.
J Vasc Res ; 40(5): 449-59, 2003.
Article in English | MEDLINE | ID: mdl-14564104

ABSTRACT

The time-course of endothelial regrowth and functional recovery following polytetrafluoroethylene filament-induced endothelial denudation in vivo was studied in the left common carotid artery of the mouse. This technique does not result in any intimal hyperplasia, enabling the investigation of endothelial function without any confounding effect of intimal thickening. Endothelial coverage was assessed histologically, and functional recovery was assessed as restoration of receptor-mediated, endothelium-dependent relaxation to acetylcholine in vitro. Re-endothelialization of the carotid artery was complete within 8 days of denudation. However, relaxations to acetylcholine, which are mediated by endothelium-derived nitric oxide, were only partially restored 10 days after the procedure. At this time point, arterial responses to either phenylephrine, the receptor-independent endothelium-dependent dilator cyclopiazonic acid, or the nitric oxide donor diethylamine NONOate, were not significantly different to controls. At 25 days after denudation, acetylcholine-evoked responses remained significantly depressed compared to controls but at 90 days full recovery was observed. These data indicate that following mechanical denudation of the mouse carotid artery, although endothelial re-growth is complete within 8 days, recovery of endothelial cell function - assessed as the ability of the regenerated endothelium to mediate acetylcholine-stimulated relaxation - remains impaired for a prolonged period.


Subject(s)
Acetylcholine/pharmacology , Carotid Arteries/drug effects , Endothelial Cells/physiology , Receptors, Cholinergic/physiology , Animals , Carotid Arteries/physiology , In Vitro Techniques , Indoles/pharmacology , Male , Mice , Mice, Inbred C57BL , Nitroarginine/pharmacology , Vasodilation/drug effects
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