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)

We studied the elasticity and endothelium-dependent relaxation (EDR) of the aorta in 1% cholesterol diet (HCD)-fed rabbits. Furthermore, the effects of ethyl all-cis-5,8,11,14, 17-icosapentaenoate (EPA-E) were examined in this model of atherosclerosis. After 12 weeks of feeding with HCD, the animals showed increase in plasma total cholesterol level, formation of atherosclerotic plaque, decrease in aortic elasticity and impairment of EDR to acetylcholine (ACh). The levels of aortic elasticity in HCD-fed rabbits administered orally with EPA-E (300 mg/kg for 12 weeks) were almost the same as those of rabbits fed a normal diet, although EPA-E showed no effects on the plasma total cholesterol level and formation of atherosclerotic plaque in HCD-fed rabbits. On EDR in response to ACh and cyclic GMP formation in the HCD-fed rabbit aorta, EPA-E improved the impairment of these parameters, but not significantly. Therefore, EPA-E had little effect on the endothelium in this model of atherosclerosis, although EPA-E improved the decrease in the aortic elasticity. Because the levels of aortic elasticity showed no significant correlation with the magnitude of EDR to ACh or the size of atherosclerotic plaque, the decrease of aortic elasticity in this model of atherosclerosis was thought to have little relation to the dysfunction of the endothelium.
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PMID:[Effects of ethyl all-cis-5,8,11,14,17-icosapentaenoate (EPA-E) on elasticity and endothelium-dependent relaxation of the aorta in high cholesterol diet-fed rabbits]. 807 89

A diminished relaxant response of atherosclerotic arteries to nitrovasodilators has been frequently observed in advanced stages of hypercholesterolemia. In the present study, we investigated whether this effect might be a result of reduced activity of smooth muscle guanylyl cyclase. Experimental atherosclerosis was induced by feeding rabbits a cholesterol-rich diet (1%) over a period of 4 months. Aortas were removed and homogenized, and guanylyl cyclase activity was measured in the 100,000 g supernatants. Sodium nitroprusside, which stimulated cyclic GMP (cGMP) formation in control tissues almost 200-fold (from 3 to 585 pmol cGMP.mg-1 x min-1), increased enzyme activities in atherosclerotic aortas only approximately 90-fold (from 3 to 257 pmol cGMP.mg-1 x min-1). Similarly, the maximal stimulatory effects of S-nitroso-glutathione were reduced from 200-fold (controls) to 114-fold in atherosclerotic tissues. Basal guanylyl cyclase activities were identical in both atherosclerotic and control vessels. Hypercholesterolemia also reduced the activity of smooth muscle adenylyl cyclase. In control aortas, basal and NaF-stimulated enzyme activities were 24 and 349 pmol cAMP.mg-1 x min-1, respectively, whereas cAMP formation was reduced in atherosclerotic aortas to 7 (basal) and 96 (NaF) pmol cAMP.mg-1.min-1. The stimulatory effect of NaF (approximately 14-fold) remained unchanged. Since adenylyl and guanylyl cyclase have important functions in regulating vascular tone, reduced activities of both enzymes may contribute to the diminished relaxant and/or enhanced vasoconstricting effects of vasoactive compounds in atherosclerotic blood vessels.
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PMID:Hypercholesterolemia is associated with a reduced response of smooth muscle guanylyl cyclase to nitrovasodilators. 810 69

We have investigated the requirement for c-myc downregulation in the growth arrest of vascular smooth muscle cells (VSMCs). Rat VSMCs were infected with a retrovirus vector directing constitutive expression of either the complete human c-Myc protein (VSM-myc cells) or the c-Myc deletion mutant D106-143, which is inactive in cotransformation and autosuppression assays (VSM-D106-143 myc cells). Clones of transfected VSM-myc cells were isolated that constitutively expressed a range of levels of c-Myc protein from that observed in normal proliferating VSMCs to approximately seven times normal. The growth rates of these clones and their responses to growth inhibitors were then assessed. VSM-myc clones possessed a shorter mean intermitotic time than normal cells, which was inversely correlated (P < .05) with the level of c-Myc protein expressed. VSM-myc cells also expressed lower levels of alpha-smooth muscle actin mRNA and protein and exhibited an altered morphology. The proliferation of normal VSMCs and VSM-D106-143 myc cells was inhibited by serum reduction (0.5% fetal calf serum) and also by treatment with interferon-gamma (100 IU/mL), heparin (50 micrograms/mL), 8-bromo-cAMP (0.1 mmol/L), or 8-bromo-cGMP (0.1 mmol/L). In contrast, proliferation of VSM-myc cells was not inhibited by any of these agents, even if present at 10-fold higher concentrations. However, approximately 75% of VSM-myc cells expressing levels of c-Myc protein seen in normal proliferating VSMCs underwent apoptosis after 4 days of serum reduction or treatment with interferon-gamma. The results show that constitutive c-myc expression induces continuous cell proliferation, reduction in alpha-smooth muscle actin expression and apoptosis in VSMCs. We conclude that downregulation of c-myc is a prerequisite for growth arrest and subsequent survival of VSMCs. Conversely, deregulated c-myc expression may be important in the proliferation and death of VSMCs--characteristics of the pathogenesis of atherosclerosis.
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PMID:Deregulated expression of the c-myc oncogene abolishes inhibition of proliferation of rat vascular smooth muscle cells by serum reduction, interferon-gamma, heparin, and cyclic nucleotide analogues and induces apoptosis. 811 60

Nitric oxide is widely distributed in the body. It has an important role in the regulation of the circulation and as yet, ill-defined roles in nervous and immune systems. It is derived from L-arginine from a reaction catalysed by a constitutive intracellular enzyme, nitric oxide synthase. It is recognised as the endogenous nitrovasodilator whose action is mimicked by all exogenous nitrovasodilators. After production in the vascular endothelial cell, it diffuses to the smooth muscle cell where it activates the enzyme guanylate cyclase which leads to an increase in cyclic GMP and thence to muscle relaxation. The duration of its action is brief, a few seconds. Disorders of NO metabolism underlie many disease states including endotoxic shock in which prolonged production of nitric oxide may be induced by cytokines. Deficiencies in endogenous production may account for hypertension in various disease states including atherosclerosis and chronic renal failure. NO therapy been used experimentally to successfully treat idiopathic pulmonary hypertension and pulmonary hypertension associated with cardiac and respiratory diseases. However, the long-term benefits have yet to be studied. Administration of NO requires the use of a device to monitor the concentrations of both NO and of NO2. The latter is a noxious agent and a time-related product of the reaction between NO and O2 and is a possible contaminant of preparations of NO. Precautions must be taken to prevent contamination of the work-place atmosphere with NO and NO2. These include gas scavenging and the use of a leak-free system for spontaneous and mechanical ventilation. Using NO in its gaseous form, clinicians have at long last been provided with the means to treat pulmonary hypertension without adversely causing systemic hypotension. The therapy is most suited to short-term use in mechanically ventilated patients. Safe practical long-term NO therapy must await the development of agents which release NO from aerosol preparations.
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PMID:The role of nitric oxide (formerly endothelium-derived relaxing factor-EDRF) in vasodilatation and vasodilator therapy. 812 32

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

Chronic rejection has been linked to premature coronary atherosclerosis in heart transplantation and may be related to altered vascular reactivity. However, the effect of acute rejection on coronary reactivity remains uncertain. To evaluate this aspect, coronary artery reactivity was studied during acute rejection in a canine model of heart transplantation. Two groups of mongrel dogs (n = 7) (20 to 30 kg) underwent heterotopic heart transplantation (cervical position), and received either no treatment (noTx) or cyclosporine (CyA), 10 mg/kg/day. On day 7, recipient native (NH) and grafted hearts (GH) were harvested and 4-mm rings from the circumflex coronary artery were studied in organ chambers for endothelium and smooth muscle reactivity. At the harvesting, GHnoTx displayed a grade IV/IV histologic rejection while GHCyA (CyA dosage 250-350 nM) reached grade IIIa-IV. Intimal hyperplasia was found in coronary arteries of treated and non-treated GH [4/7 (noTx) vs 3/7 (CyA)]. Endothelium-dependent relaxation to thrombin was impaired in GH compared to NH and was not influenced by CyA treatment [EC50 (-log M): GHnoTx: 1.12 +/- 0.18 vs NHnoTx: 1.67 +/- 0.16 (p = 0.06); GHCyA: 0.99 +/- 0.22 vs NHCyA: 1.64 +/- 0.09 (p = 0.02)]. Conversely, endothelium-dependent relaxation to 5-hydroxytryptamine (5-HT) was enhanced in both CyA-treated and noTx groups [EC50 (-log M); GHnoTx: 5.96 +/- 0.12 vs NHnoTx: 5.54 +/- 0.14 (p = 0.046); GHCyA: 6.65 +/- 0.19 vs NHCyA: 5.66 +/- 0.16 (p = 0.004)]. A facilitating effect of CyA on 5-HT was also seen in GH [GHnoTx vs GHCyA (p = 0.01)], suggesting a CyA intrinsic effect. Responses to acetylcholine and adenosine diphosphate were similar in all groups as well as endothelium-independent relaxation to sodium nitroprusside and contractile response to KCl and PGF2 alpha. We conclude that, in our model, acute rejection does not specifically impair cGMP-mediated relaxation but affects in a receptor-specific manner the endothelium-dependent relaxation. CyA did not prevent these effects but furthermore appeared to enhance the coronary endothelial sensitivity to 5-HT.
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PMID:[Effects of acute rejection on the endothelium-dependent relaxation of coronary arteries of the transplanted heart in dogs]. 856 29

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
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PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

Recent evidence suggests that nitric oxide (NO) may function as a second messenger in the intracellular signal transduction pathways. We explored the possibility that NO was involved in the signal for triggering apoptosis in smooth muscle cells (SMCs). Chemical NO donors induced SMCs apoptosis in a concentration- and time-dependent manner. The membrane-permeable cGMP analogue, dibutyryl-cGMP, did not induce SMCs apoptosis, and the highly selective inhibitor of cGMP-dependent protein kinase, KT5823, was unable to inhibit the induction of NO-induced SMCs apoptosis. Inhibitor of ADP-ribosyltransferase slightly attenuated the induction of SMCs apoptosis by S-nitroso-N-acetyl penicillamine (SNAP). The inhibitor of Na+-H+ antiporter, amiloride, completely inhibited the induction of SMCs apoptosis by SNAP. These results demonstrate for the first time that NO can induce apoptosis in SMCs, suggesting that NO acts as a mediator in the development of atherosclerosis lesion via alterations in the number of SMCs. In addition, the results suggest that NO exert these effects through a pathway that does not involve guanylate cyclase and cGMP-dependent protein kinase.
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PMID:Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP-independent mechanism. 866 Mar 29

Nitric oxide (NO), the biologically active component of endothelium-derived relaxing factor, has critical roles in the maintenance of vascular homeostasis. Decreased endothelial NO production, as a result of endothelial dysfunction, occurs in the early phases of atherosclerosis. NO appears to inhibit atherogenesis by inhibiting leukocyte and platelet activation and by inhibiting smooth muscle cell proliferation. Endothelial denudation is a prominent feature of vascular injury associated with percutaneous angioplasty, and decreased NO production appears to contribute to the restenosis process. Manipulation of the NO/cGMP signal transduction system may provide novel therapeutic approaches for limiting atherogenesis and neointimal proliferation in the future.
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PMID:The vascular biology of nitric oxide and its role in atherogenesis. 871 88

Since endothelium-dependent vasodilation is altered in atherosclerosis and enhanced monocyte/endothelial interactions are implicated in early atherosclerosis, we evaluated the effects of monocytes on the endothelial nitric oxide (NO) pathway by estimating release of biologically active NO from cultured endothelial cells and levels of constitutive NO synthase (ecNOS). NO release was estimated in a short-term bioassay using endothelial cell-induced cGMP accumulation in vascular smooth muscle (SM) cells. Exposure of SM cells to porcine aortic endothelial cells (PAECs) and human aortic endothelial cells (HAECs) produced large increases in SM cGMP content; this increase was prevented by NG-nitro-L-arginine methyl ester, the inhibitor of endothelial NOS. Confluent monolayers of PAECs and HAECs cocultured with monocytes also stimulated SM cGMP formation; however, NO release from these cultures was attenuated in a coculture time (2 to 48 hours)- and monocyte concentration (20 to 200 x 10(3) per well)-dependent manner. This effect of monocyte adhesion appeared to be selective for NO release since other biochemical pathways, such as atriopeptin-and isoproterenol-induced cyclic nucleotide accumulation within the endothelial cells, were not altered by monocytes. The effects of adherent monocytes on NO release were mimicked by monocyte-derived cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 alpha. Furthermore, the conditioned medium of monocytes contained significant quantities of these cytokines. Conditioned medium, as well as monocytes physically separated from the endothelial cells, attenuated NO release, suggesting that soluble factors may mediate the effects of monocytes. An IL-1 beta neutralizing antibody fully prevented the NO dysfunction in response to directly adherent monocytes. Superoxide dismutase, catalase, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), and exogenous L-arginine failed to improve NO release, suggesting that oxidant stress-induced inactivation of NO or limited substrate availability were not primarily responsible for the inhibiting effects of monocytes. Western blot analysis revealed reduced quantities of ecNOS in monocyte/endothelium cocultures, as well as in HAECs treated with monocyte-conditioned medium or TNF-alpha. Thus, adhesion of monocytes to endothelial cells and monocyte-derived secretory products downregulate steady state levels of ecNOS, an event associated with attenuated release of biologically active NO. This mechanism may potentially contribute to diminished endothelium-dependent and NO-mediated vasodilation in early atherosclerosis.
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PMID:Monocyte-induced downregulation of nitric oxide synthase in cultured aortic endothelial cells. 879 62


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