Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of serotonin on migration of cultured rat aortic smooth muscle cells (SMC) were studied to clarify the role of this substance in the pathogenesis of atherosclerosis. Serotonin alone did not stimulate SMC migration but stimulated it at physiological concentrations in the presence of other migration factors such as SMC-derived migration factor, platelet-derived migration factor and fibronectin. Checker-board analysis revealed that the serotonin effect was chemotactic. Moreover, serotonin effects were completely abolished by a selective inhibitor of the 5-HT2 receptor (MCI-9042), indicating that serotonin effects were mediated through the 5-HT2 receptor pathway. Finally, serotonin effects were also abolished by a phospholipase C inhibitor, U73122, suggesting that the 5-HT2 receptor mediated signal of serotonin was transduced by PLC. The results suggest that platelet-derived serotonin plays some role in the SMC dominant neointima formation.
Atherosclerosis 1997 Jul 25
PMID:Serotonin (5-hydroxytryptamine, 5-HT) enhances migration of rat aortic smooth muscle cells through 5-HT2 receptors. 924 58

Little is known about how the vascular reactivity of the coronary microcirculation is affected by upstream atherosclerotic disease. We have examined, with a wire myograph, the responses of intramyocardial arteries from hearts in which the epicardial vessels were either free of atherosclerotic lesions (non-diseased group) or were affected by atherosclerosis (diseased group). Vasodilator responses of preconstricted vessels to substance P (84.1 +/- 12.6 compared to 42.0 +/- 19.7%) were less in vessels from the diseased group (p < 0.05). In contrast, the relaxation to bradykinin (70.2 +/- 21.2 compared to 100.6 +/- 7.9%) was increased in vessels from the diseased group (p < 0.05). The dilator responses to acetylcholine, adenosine diphosphate, histamine and sodium nitroprusside showed no significant differences between arteries from each group. 5-Hydroxytryptamine was without any significant vasodilator effect in arteries from either group. Assessment of contractile function revealed that the responses to 5-hydroxytryptamine, acetylcholine, U46619, endothelin-1 and L-N(G)-monomethylarginine in each group were not significantly different. Histamine, noradrenaline and dopamine were without any significant contractile response. These results demonstrate that upstream atherosclerosis does not confer any global impairment of endothelium-dependent vasorelaxant responses or smooth muscle hyperreactivity to vasoconstrictors in the arteries that penetrate the myocardium.
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PMID:Reactivity of small intramyocardial arteries from atherosclerotic and non-atherosclerotic human hearts. 964 31

Serotonin (5HT) released from aggregating platelets at sites of vascular injury is a known mitogen for vascular endothelial cells. Recent studies have indicated that regenerating endothelial cells at sites of vessel wall injury may play a role in the development of restenosis by synthesizing and releasing growth factors for vascular smooth muscle cells, proliferation of which may result in the development of neointima. Diets rich in fish oils (omega-3 fatty acids) are associated with reduced risk of cardiovascular disease including atherosclerosis and restenosis. This study examined the effect of the omega-3 and other fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on 5HT induced endothelial cell proliferation. Among the fatty acids examined only EPA and DHA could reverse the mitogenic effect of 5HT on vascular endothelial cells, whereas oleic acid or palmitic acid did not have any effect. When added together, EPA and DHA potentiate each other in reversing the mitogenic effect of 5HT. EPA and DHA also inhibited the 5HT-induced increase in the 5HT2 receptor mRNA, without a change in the receptor density or affinity. This data suggests that one of the mechanisms by which omega-3 fatty acids may attenuate the development of atherosclerosis or restenosis is to inhibit the mitogen induced growth of vascular endothelial cells, which attenuates the release of growth factors for vascular smooth muscle cells.
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PMID:Serotonin-induced endothelial cell proliferation is blocked by omega-3 fatty acids. 1032 32

In humans intimal thickening is aprerequisite of atherosclerosis. Application of a silicone collar around the rabbit carotid artery induces an intimal thickening but in addition it increases the sensitivity to the vasoconstrictor action of serotonin (5-hydroxytryptamine, 5-HT). The 5-HT receptors involved in collar-induced hypersensitivity to 5-HT were investigated using several agonists and antagonists. One week after placement of collars around both carotid arteries of anaesthetized rabbits, rings (2 mm width) from inside (=collar) and outside (=sham) the collars were mounted in organ baths (10 ml) for isometric force measurements at 6 g loading tension. Collared rings were more sensitive to the contractile effect of 5-HT (7.6 fold) and 5-carboxamidotryptamine (31 fold, 5-CT, 5-HT1 agonist) in cumulative concentration response curves. Sumatriptan (5-HT1B/1D agonist) caused concentration-dependent constrictions in collared rings only. Collar placement did not significantly alter pA2 values (Schild regression) or apparent pKb values (non-linear regression) of spiperone and methysergide (mixed 5-HT2A/5-HT1 antagonists) or ketanserin and ritanserin (5-HT2A antagonists), indicating unchanged binding characteristics of the 5-HT2A receptor. However, the reduced slope of the Schild regression pointed to a heterogeneous receptor population in collared rings. In contrast, the apparent pKb value of methiothepin (5-HT1B antagonist) was significantly reduced by collar placement, and its antagonism shifted from non-surmountable in sham rings to surmountable in collared segments. Taken together, this study demonstrates that the serotonergic receptor involved in the hypersensitivity to 5-HT of rabbit collared carotid artery is a 5-HT1B receptor subtype.
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PMID:Involvement of 5-HT1B receptors in collar-induced hypersensitivity to 5-hydroxytryptamine of the rabbit carotid artery. 1045 82

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) present in fish oils have been ascribed as having significant antithrombotic and antiatherosclerotic effects. Vascular smooth muscle cell (SMC) proliferation plays an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have indicated that serotonin at concentrations present at sites of vascular injury stimulates SMC proliferation and may contribute to the restenotic process. In the present study we demonstrate that among the fatty acids tested, only EPA and DHA could block the mitogenic effect of serotonin on vascular SMC. Further, when added together these fatty acids act synergistically in blocking the mitogenic effect of serotonin. EPA and DHA blocked the 5HT-induced increase in the 5-HT(2) receptor mRNA. This antimitogenic effect of EPA and DHA may partially explain some of the beneficial effects of fish oils.
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PMID:Eicosapentaenoic acid and docosahexaenoic acid block serotonin-induced smooth muscle cell proliferation. 1052 59

Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 microg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) N(G)-monomethyl-L-arginine (L-NMMA; 2, 4, and 8 micromol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 microg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers.
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PMID:Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. 1066 24

So far it is not clear how erythropoietin affects the anticoagulant properties of vascular endothelium in uremia. Since serotonin is also thought to play a role in the pathogenesis of thrombosis, the aim of the study was to evaluate major components of extrinsic coagulation pathway, markers of endothelial cell injury, lipoprotein (a) and peripheral serotonergic mechanisms during rHuEPO therapy in hemodialyzed patients. The study was performed on chronically hemodialyzed patients divided into two groups: with rHuEPO treatment and without rHuEPO therapy in relation to the control group. In uremic patients, thrombomodulin and von Willebrand factor, activity of factor VII, tissue factor pathway inhibitor (TFPI) activity, TFPI and tissue factor (TF) concentrations, lipoprotein (a) level were significantly higher when compared to healthy volunteers. Treatment with rHuEPO resulted in a further significant rise in markers of endothelial cell injury: thrombomodulin and von Willebrand factor and TFPI concentration. Extrinsic coagulation factors: activities of factor VII and X, TFPI activity and TF activity and concentration, lipoprotein (a) and vitronectin remained unchanged during rHuEPO therapy. Platelet serotonin content and whole blood serotonin were significantly lower in uremic patients relative to healthy volunteers and during rHuEPO treatment they increased significantly. Whole blood serotonin reached normal values. Plasma serotonin, significantly elevated in uremia, did not change during rHuEPO therapy. Serotonin uptake by uremic platelets was significantly impaired and remained unaltered during rHuEPO administration. Serotonin release by uremic platelets was also significantly depressed but a significant improvement was observed in rHuEPO-treated patients. Our data suggest that endothelial injury, TF pathway components and peripheral serotonergic system disturbances may predispose to thromboembolic complications and play a role in the pathogenesis of atherosclerosis in uremic patients, particularly treated with rHuEPO. Increase in TFPI may compensate the increase in TF in these patients.
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PMID:Importance of serotonergic mechanisms in the thrombotic complications in hemodialyzed patients treated with erythropoietin. 1075 6

Serotonin (5-HT), released from activated platelets, has been implicated in the pathogenesis of acute myocardial infarction (AMI). 5-HT induces platelet aggregation and vascular contraction through 5-HT2A receptor activation at sites of coronary atherosclerosis, leading to thrombus formation. Recently, a 5-HT2A receptor gene T102C polymorphism has been reported to be associated with clinical response to 5-HT2A receptor antagonist in patients with schizophrenia, suggesting this polymorphism of the gene affects the 5-HT2A receptor function. To investigate the relationship between the T102C polymorphism and AMI, we conducted a case-control study of 255 non-fatal AMI patients and 255 control subjects. Among the patients, the prevalence of TT genotype was significantly higher than in controls (32.5 vs. 24.3%; P<0.05). In male patients (n=216), the prevalence was much higher than in control subjects (33.8 vs. 24. 1%, P<0.03). In multiple logistic regression models, odds ratio of TT genotype was 1.45 (95% CI 0.96-2.20) in all and 1.61 (95% CI 1. 03-2.53) (P<0.05) in males. The association of T102C polymorphism of the 5-HT2A receptor gene with non-fatal AMI was statistically significant and independent of other risk factors in males. The TT genotype of the 5-HT2A receptor gene may enhance susceptibility to AMI. Our observations suggest that the T102C polymorphism of the 5-HT2A receptor gene can serve as a new genetic marker for AMI.
Atherosclerosis 2000 May
PMID:T102C polymorphism of the serotonin (5-HT) 2A receptor gene in patients with non-fatal acute myocardial infarction. 1078 45

Previous studies have reported the development of vasoconstriction immediately after invasive coronary interventions. Other studies in animals have demonstrated that using oversized balloon angioplasty, vasospasm can be suppressed, even in the presence of endothelial denudation due to important structural alteration in vascular smooth muscle. The regenerated endothelium also appears to be impaired chronically by selective attenuation of in vitro endothelial dependent relaxation related to pertussis toxin-sensitive G proteins. The purpose of this investigation was to verify in vivo and in vitro vasoreactivity to bradykinin (BK) and serotonin (5-hydroxytryptamine; 5-HT) (endothelial dependent agonists) as well as to nitroglycerin (NTG) (exogenous nitric oxide donor) at different times after oversized balloon angioplasty intervention ranging from 1 h to 12 weeks, in normal porcine coronary arteries. BK-induced vasodilatation in vivo was impaired acutely, but it was restored after 4 weeks. Serotonin caused vasoconstriction in vivo that was significantly augmented after 12 weeks. Conversely, endothelium-dependent vasodilatation in vitro to BK and 5-HT remained attenuated during the whole period of follow-up. Finally, relaxation elicited by NTG was reduced in the in vivo experiment until the first week after the procedure. Histological analysis showed severe arterial injury, and complete recovery of endothelial coverage after 4 weeks. In conclusion, this experiment supports evidence for the occurrence of the acute attenuation of vasoresponsiveness and chronic endothelial dysfunction following overstretching coronary balloon angioplasty. Abnormal remodeling associated with the severity of injury may contribute to chronic endothelial dysfunction. Differences found between in vivo and in vitro studies also suggest that multiple endogenous influences present in the former can attenuate the greater endothelial dysfunction demonstrated by endothelial assessment in vitro.
Atherosclerosis 2001 Jan
PMID:Chronic endothelial dysfunction after oversized coronary balloon angioplasty in pigs: a 12-week follow-up of coronary vasoreactivity in vivo and in vitro. 1113 83

Formation of an atherosclerotic lesion is in part mediated by inflammatory and oxidative mechanisms including lipid peroxidation. To characterize the potential role of lipid peroxidation products in atherogenesis, we assessed the effect of 4-hydroxy-2-nonenal (HNE), a component of oxidatively modified lipids on vascular smooth muscle cells (VSMCs) proliferation, and its interaction with serotonin (5-hydroxytryptamine, 5-HT), a known mitogen for VSMCs. Growth-arrested rabbit VSMCs were incubated with different concentrations of HNE in the absence or presence of 5-HT. VSMCs proliferation was examined by increases in [3H]thymidine incorporation into DNA and cell number. HNE and 5-HT stimulated DNA synthesis in a dose-dependent manner. HNE had a maximal proliferative effect at a concentration of 1 microM (143% of the control) and 5-HT at 50 microM (211%). When added together, low concentrations of HNE (0.1 microM) and 5-HT (5 microM) synergistically induced DNA synthesis (273%). These effects on DNA synthesis were paralleled by an increase in cell number. A 5-HT2 receptor antagonist LY 281067 (10 microg/ml) and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT only. Protein tyrosine kinase inhibitor erbstatin A (10 microM) completely inhibited the mitogenic effect of HNE and partially that of 5-HT and the combined effect of HNE+5-HT. Protein kinase C inhibitor Ro 31-8220 (0.1 microM) completely inhibited mitogenic effects of both HNE and 5-HT, and also the combined effect of HNE+5-HT. The synergistic effect of HNE+5-HT on DNA synthesis was completely reversed by the combined use of LY 281067 (10 microg/ml) and antioxidants N-acetylcysteine (400 microM), vitamin C (200 microM), or vitamin E (20 microM). Our results suggest that HNE acts synergistically with 5-HT in inducing VSMCs proliferation. Combined use of both antiplatelet and antioxidant therapies may be useful for the prevention of VSMCs proliferative disorders associated with atherosclerosis and restenosis after angioplasty.
Atherosclerosis 2001 Mar
PMID:Lipid peroxidation product 4-hydroxy-2-nonenal acts synergistically with serotonin in inducing vascular smooth muscle cell proliferation. 1122 24


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