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)

Correlative studies have indicated that hyperinsulinemia is present in many individuals with atherosclerosis. Insulin resistance has also been linked to cardiovascular disease. It has proved to be difficult to decipher whether hyperinsulinemia or insulin resistance plays the most important role in the pathogenesis of atherosclerosis and coronary artery disease. In this study, we demonstrate that insulin increases the amount of farnesylated p21Ras in vascular smooth muscle cells (VSMC), thereby augmenting the pool of cellular Ras available for activation by platelet-derived growth factor (PDGF). In VSMC incubated with insulin for 24 h, PDGF's influence on GTP-loading of Ras was significantly increased. Furthermore, in cells preincubated with insulin, PDGF increased thymidine incorporation by 96% as compared with a 44% increase in control cells (a 2-fold increment). Similarly, preincubation of VSMC with insulin increased the ability of PDGF to stimulate gene expression of vascular endothelial growth factor 5- to 8-fold. The potentiating influence of insulin on PDGF action was abrogated in the presence of a farnesyltransferase inhibitor. Thus, the detrimental influence of hyperinsulinemia on the arterial wall may be related to the ability of insulin to augment farnesyltransferase activity and provide greater amounts of farnesylated p21Ras for stimulation by various growth promoting agents.
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PMID:Insulin potentiates platelet-derived growth factor action in vascular smooth muscle cells. 975 84

The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many patients. The development of the HMG-CoA reductase inhibitors (statins) have been a major advance in that they possess multiple pharmacological effects (pleiotropic effects) resulting in potent reductions of low density lipoproteins (LDL) and prevention of the atherosclerotic process. More recently, the newer fibric acid derivatives have also reduced LDL to levels comparable to those achieved with statins, have reduced triglycerides, and gemfibrozil has been shown to increase high density lipoprotein (HDL) levels. Nicotinic acid has been made tolerable with sustained-release formulations, and is still considered an excellent choice in elevating HDL cholesterol and is potentially effective in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk factor for coronary heart disease (CHD). Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic agents may have directly or indirectly targeted thrombogenic, fibrinolytic and atherosclerotic processes which may have been unaccounted for in their overall success in clinical trials. Although LDL cholesterol is still the major target for therapy, it is likely that over the next several years other lipid/lipoprotein and nonlipid parameters will become more generally accepted targets for specific therapeutic interventions. Some important emerging lipid/lipoprotein parameters that have been associated with CHD include elevated triglyceride, oxidised LDL cholesterol and Lp(a) levels, and low HDL levels. The nonlipid parameters include elevated homocysteine and fibrinogen, and decreased endothelial-derived nitric oxide production. Among the new investigational agents are inhibitors of squalene synthetase, acylCoA: cholesterol acyltransferase, cholesteryl ester transfer protein, monocyte-macrophages and LDL cholesterol oxidation. Future applications may include thyromimetic therapy, cholesterol vaccination, somatic gene therapy, and recombinant proteins, in particular, apolipoproteins A-I and E. Non-LDL-related targets such as peroxisome proliferator-activating receptors, matrix metalloproteinases and scavenger receptor class B type I may also have clinical significance in the treatment of atherosclerosis in the near future. Before lipid-lowering therapy, dietary and lifestyle modification is and should be the first therapeutic intervention in the management of dyslipidaemia. Although current recommendations from the US and Europe are slightly different, adherence to these recommendations is essential to lower the risk of atherosclerotic vascular disease, more specifically CHD. New guidelines that are expected in the near future will encompass global opinions from the expert scientific community addressing the issue of target LDL goal (aggressive versus moderate lowering) and the application of therapy for newer emerging CHD risk factors.
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PMID:Current, new and future treatments in dyslipidaemia and atherosclerosis. 1092 30

A number of primary and secondary prevention studies with HMG-CoA reductase inhibitors(statins) have shown a reduction of cardiac events. However, such cardiac events cannot be completely prevented by antihyperlipidemic drugs there are a number of patients whose hyperlipidemia is resistant to conventional treatment. Furthermore, it is still difficult to observe a regression of atherosclerosis even when patients become normolipidemic after treatment. Thus, many antihyperlipidemic drugs with novel mechanisms are under development and are expected to inhibit progression or rather obtain regression of atherosclerosis in clinical settings. In the current review, inhibitors of cholesterol synthesis such as squalene synthase and squalene epoxidase inhibitors, ileal Na+/bile acid cotransporter(IBAT) inhibitors, and inhibitors of intestinal cholesterol absorption are described.
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PMID:[Trends toward development of other novel antihyperlipidemic drugs]. 1203 3

Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.
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PMID:Squalene epoxidase as hypocholesterolemic drug target revisited. 1246 39

Accumulation of lipids and cholesterol by macrophages and subsequent transformation into foam cells are key features in development of atherosclerosis. Serum copper concentrations have been shown to be associated with cardiovascular disease. However, the mechanism behind the proatherogenic effect of copper is not clear. We used DNA microarrays to define the changes in gene expression profile in response to copper exposure of human macrophages. Expression monitoring by DNA microarray revealed 91 genes that were regulated. Copper increased the expression of seven cholesterogenic genes (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, IPP isomerase, squalene synthase, squalene epoxidase, methyl sterol oxidase, H105e3 mRNA and sterol-C5-desaturase) and low-density lipoprotein receptor (LDL-R), and decreased the expression of CD36 and lipid binding proteins. The expression of LDL-R and HMG CoA reductase was also investigated using real time PCR. The expression of both of these genes was increased after copper treatment of macrophages (P<0.01 and P<0.01, respectively). We conclude that copper activates cholesterogenic genes in macrophages, which may provide a mechanism for the association between copper and atherosclerosis. The effect of copper on cholesterogenic genes may also have implications for liver steatosis in early stages of Wilson's disease.
Atherosclerosis 2003 Jul
PMID:Copper induces the expression of cholesterogenic genes in human macrophages. 1286 Feb 52

Lipid-lowering is established as a proven intervention to reduce atherosclerosis and its complications. This article summarises imminent developments in lipid-lowering therapy, including new statins and cholesterol absorption inhibitors currently undergoing investigation for licensing. It also discusses other therapeutic targets such as squalene synthase, microsomal transfer protein (MTP), acyl-cholesterol acyl transferase (ACAT), cholesterol ester transfer protein (CETP), peroxosimal proliferator activating receptors (PPARs) and lipoprotein (a) (LP(a)), for which compounds have been developed and have at least reached trials in animal models. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
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PMID:New lipid-lowering agents. 1466 95

Since we recently demonstrated that high-density lipoprotein induced human coronary artery endothelial cell (HCEC) tube formation through Ras/Raf/ERK (extracellular-signal-regulated kinase) activation [Arterioscler. Thromb. Vasc. Biol. 23 (2003) 802], it is possible that lipid-lowering agents such as statins, which reduce the prenylation of Ras, could decrease such tube formation. Therefore, we investigated whether this event occurs through inhibition of the Ras/Raf/ERK pathway. We developed an in vitro model of EC tube formation on a matrix gel. Simvastatin inhibited serum-induced endothelial tube formation after 18 h. The inhibition of ERK activity suppressed serum-induced tube formation. Farnesylpyrophosphate (Fpp), which translocates Ras from the cytoplasm to the cell membrane, rescued this inhibition. In addition, farnesyltransferase I inhibitor, which inhibits Ras farnesylation, and dominant-negative Ras (N17) also inhibited serum-induced tube formation. Although Fpp activated Ras assessed by a Ras pull-down assay and phospho(p)-ERK1/2, Fpp-induced p-ERK1/2 activation was not inhibited by simvastatin. In conclusion, simvastatin-induced Ras/Raf/ERK inactivation is a potent signal in the anti-angiogenic phenotype of HCECs. Fpp counteracted simvastatin-induced Ras/Raf/ERK inactivation.
Atherosclerosis 2004 Aug
PMID:Simvastatin suppresses coronary artery endothelial tube formation by disrupting Ras/Raf/ERK signaling. 1526 79

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).
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PMID:[Cholesterol metabolism modulators and the future of atherosclerosis therapy]. 1532 20

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development, including combination therapies, squalene synthase inhibitors, microsomal transfer protein inhibitors, acyl-cholesterol acyl transferase inhibitors, cholesterol ester transfer protein antagonists, peroxisome proliferator-activated receptor agonists, high-density lipoprotein-derived peptides and inflammation inhibitors, which have at least reached trials in animal models. Lipid-altering drugs are likely to to be a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis. New agents will have to show significant advantage in tolerability or efficacy over existing agents and have the potential to be used in combination therapy as is well established for bile acid sequestrants, nicotinic acid or fibrates and statins. Any new drugs will also have to be assessed in clinical end-point trials against current compounds with proven outcome benefits.
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PMID:Lipid-lowering therapies in development. 1550 Mar 89

Lipid-lowering is established as proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development. It also discusses other therapeutic targets, such as squalene synthase, microsomal transfer protein, acyl-cholesterol acyl transferase, cholesterol ester transfer protein, peroxosimal proliferator-activating receptors and lipoprotein (a), for which compounds have been developed and have at least reached trials in animal models. Lipid-altering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
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PMID:Lipid-altering agents: the future. 1560 75


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