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 mechanism of the progression of atherosclerosis involves the rupture of a plaque with thrombus formation, followed by an invasion of monocytes that induce the formation of tissue factor and a second thrombus. This is followed by activation of the smooth muscle cells of the arterial wall with formation of connective tissue that infiltrates both thrombi. We can try to prevent atherosclerosis progression by inhibiting thrombosis with an inhibitor of tissue factor, inhibiting the process of scarring with Rapamycin, or both. Nowadays, we can study these processes using highly sensitive techniques to monitorize the formation and evolution of the thrombus, and magnetic resonance imaging that allow us to study the growth of the connective tissue. With these techniques we can study the natural history of atherosclerosis and the efficacy of different drugs to prevent its progression.
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PMID:[Thrombus remodeling. Key factor in the progression of coronary atherosclerosis]. 1100 62

Smooth muscle cell (SMC) proliferation is a prominent feature of intimal hyperplasia after percutaneous coronary interventions. p27 is a critical regulator of cell proliferation. Our aims were to analyze the time course of p27 expression, Ki67 proliferative index, and apoptosis after angioplasty in the porcine coronary artery. We also investigated the effects of rapamycin--an antiproliferative drug--on these events. The expression of p27 and Ki67, and apoptosis were determined in porcine coronary arteries harvested at timed intervals from 1 h to 28 days after angioplasty. A gradual increase in p27 expression was observed from 7 to 28 days. Ki67 expression peaked by 7-14 days after angioplasty. By 21-28 days, Ki67 expression decreased, while p27 reached maximal levels. An early apoptotic response was found by 6 h, followed by a gradual return to baseline. Rapamycin induced a reduction in Ki67 proliferative index (2 +/- 0.5%) and an increase in apoptosis (7 +/- 1%) versus untreated animals at the 28-day time point (5 +/- 1 and 1 +/- 0.5%, respectively; P < 0.05). In summary, coronary angioplasty induced a rapid apoptotic response, followed by a progressive increase in proliferation. Later on, as p27 expression increased in the vessel wall, cell proliferation decreased. Modulation of cell cycle progression may be a useful therapeutic approach in the treatment of intimal hyperplasia after angioplasty.
Atherosclerosis 2000 Dec
PMID:Modulation of apoptosis, proliferation, and p27 expression in a porcine coronary angioplasty model. 1116 20

Hyperinsulinemia has been shown to be associated with diabetic angiopathy. Migration and proliferation of vascular smooth muscle cells (VSMC) are the processes required for the development of atherosclerosis. In this study, we attempted to determine whether insulin affects mitogenic signaling induced by platelet-derived growth factor (PDGF) in a rat VSMC cell line (A10 cells). PDGF stimulated DNA synthesis which was totally dependent on Ras, because transfection of dominant negative Ras resulted in complete loss of PDGF-stimulated DNA synthesis. Initiation of DNA synthesis was preceded by activation of Raf-1, MEK and MAP kinases (Erk 1 and Erk2). Treatment of the cells with PD98059, an inhibitor of MAPK kinase (MEK) attenuated but did not abolish PDGF-stimulated DNA synthesis, suggesting that MAPK is required but not essential for DNA synthesis. PDGF also stimulated phosphorylation of protein kinase B (Akt/PKB) and p70 S6Kinase (p70S6K) in a wortmannin-sensitive manner. Rapamycin, an inhibitor of p70S6K, markedly suppressed DNA synthesis. Low concentrations of insulin (1-10 nmol/l) alone showed little mitogenic activity and no significant effect on MAPK activity. However, the presence of insulin enhanced both DNA synthesis and MAPK activation by PDGF. The enhancing effect of insulin was not seen in cells treated with PD98059. Insulin was without effect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We conclude that insulin, at pathophysiologically relevant concentrations, potentiates the PDGF-stimulated DNA synthesis, at least in part, by potentiating activation of the MAPK cascade. These results are consistent with the notion that hyperinsulinemia is a risk factor for the development of atherosclerosis.
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PMID:Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. 1199 Nov 99

Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.
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PMID:Cardiovascular toxicities of immunosuppressive agents. 1239 86

Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE, Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-gamma and IL-10 mRNA. In contrast, TGF-beta1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.
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PMID:Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice. 1275 12

Chronic inflammatory responses involving the immune system have been implicated in the process of atherosclerosis. Sirolimus (Rapamycin, Rapamune), a potent immunosuppressant used to prevent rejection of transplanted kidneys, has also proven effective at inhibiting restenosis in humans when eluted from implanted stents. The aim of this study was to evaluate the effect of sirolimus treatment on the development of atherosclerosis in the aortic arch of apo E-/- mice fed a high-fat (Western) diet. Following 12 weeks of treatment with sirolimus (4 mg/kg/d), the cholesterol content of the arch was reduced by 36% compared to untreated control mice fed the Western diet only. Although the murine model is not comparable to the human situation, the results of this study suggest that sirolimus may exert beneficial effects on atherosclerosis in transplant patients.
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PMID:Effect of sirolimus on the cholesterol content of aortic arch in ApoE knockout mice. 1469 97

Atherosclerosis is the most common cause of peripheral arterial disease (PAD). Interventional procedures are the first treatments proposed for most PAD patients. Balloon angioplasty alone may offer good immediate results; however, has it been proposed that the addition of stents improves the procedural success of angioplasty and extends its application to more types of lesions. Isolated aortic lesions are relatively rare, and the indications for stent placement have not been established. Percutaneous transluminal recanalization of chronic iliac occlusions remains controversial. However, results of recent studies have been encouraging, with initial technical success rates greater than 90%, low complication rates, and good long-term results. About the use of stent in atherosclerotic lesions involving iliac arteries and upper region of femoral arteries, we think that it is feasible. Differently, for the lower region of the femoral artery and for the popliteal artery, the results on the use of stents are controversial. More difficult is the therapy of infrapopliteal arteries disease in which perhaps the best option is medical therapy. The Transatlantic Inter-Society Consensus Group summarized the results of femoropopliteal stenting as follows: in a comparison of 11 trials involving femoropopliteal artery stenting in 585 patients, the primary patency rate was 58% at 36 months. For percutaneous transluminal angioplasty, the patency rates were 51% at 36 months. Although the results are satisfactory in femoral lesions, especially in stenoses shorter than 10 cm, they are less favorable both in longer femoral lesions than in the popliteal artery, where the results were worst. Large clinical series after angioplasty of lower limb arteries have confirmed the clinical and economical impact of restenosis: its rate varies in a range between 30% and 50%. The restenosis after stent deployment is the result of neointima formation; therefore, the interest of investigators turned towards an agent to suppress neointimal growth and restenosis after stent deployment, as Sirolimus and/or Taxolo. The first multicenter, randomized study, evaluating the 6-month outcomes of drug-eluting stent implantation in long-segment obstructions of the superficial femoral artery, was SMART trial, published in 2002. This is the first trial to show that controlled drug release is also feasible using a self-expandable nitinol stent platform. The results at 6 months demonstrate inhibition of in-stent neointimal proliferation, reflecting a trend toward a reduction in late loss.
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PMID:Molecular mechanisms of restenosis after percutaneous peripheral angioplasty and approach to endovascular therapy. 1537 21

The recent fervor surrounding the introduction of drug-eluting stents into the practice of cardiology has proven to be problematic. The experience with the Cypher Sirolimus-Eluting Coronary Stent (Cordis Corp., Miami Lakes, FL) at Arkansas Heart Hospital progressed from anxious anticipation to complete removal of the stent from inventory in a 6-month period. Several cases involving edge dissection and subacute thrombosis were the catalyst for the decision to cease use of the device. While new products may entice, each new modality must be approached with measured enthusiasm. Drug-eluting stents are first-generation devices that may have unexposed flaws when used as first-line treatment in routine practice. The first-generation Cypher stent, as with many new devices, offers treatment-not a cure-for coronary atherosclerosis and enhances the desire for an evolved product.
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PMID:Drug-eluting stents: some first-generation problems. 1560 48

Rapamycin (Sirolimus) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of rapamycin treatment, and frequently leads to cardiovascular disease. Adipocyte fatty acid binding protein (aP2) is a member of the cytoplasmic fatty acid binding protein (FABP) family. aP2 has been shown to affect insulin sensitivity, lipid metabolism, lipolysis, and has recently been shown to play an important role in atherosclerosis. We found that aP2 messenger RNA (mRNA) was increased in human THP-1 cells after rapamycin treatment. Exposure of human differentiated THP-1 cells to rapamycin led to a time- and dose-dependent induction of aP2 mRNA expression. While aP2 expression was undetectable in undifferentiated THP-1 cells, aP2 was induced in these cells by rapamycin. These data suggest that rapamycin-induced aP2 may play a role in increased triglyceride accumulation.
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PMID:Sirolimus upregulates aP2 expression in human monocytes and macrophages. 1568 34

Lipoprotein abnormalities are present in a high proportion of renal transplant patients. It is accepted that dyslipidemia is associated with atherosclerosis and in the progression of renal disease. Lipid abnormalities may also play a significant role in the development of chronic allograft nephropathy. Sirolimus was found to have an antiatherosclerotic effect in the apolipoprotein E-knockout mice model of hyperlipidemia through its antiproliferative effects. As lipid-mediated renal injury is important in the pathogenesis of glomerulosclerosis which shares common pathogenic mechanisms with atherosclerosis, in this study we have tested the hypothesis that sirolimus prevents lipid-mediated renal injury through the modulation of cholesterol homeostasis of mesangial cells and its anti-inflammatory effects on macrophages. We demonstrated that sirolimus reduced lipid accumulation, as measured by oil red O staining in human mesangial cells (HMCs). Using real-time PCR, we screened the mRNA expression of lipoprotein receptors. Sirolimus significantly suppressed LDL and VLDL receptors and CD36 gene expression. It also increased cholesterol efflux from HMCs by increasing peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARgamma, liver X receptor-alpha, and ATP binding cassette A1 (ABCA1) gene expression. Sirolimus overrode the suppression of cholesterol efflux and ABCA1 gene expression induced by the inflammatory cytokine IL-1beta. Furthermore, sirolimus significantly inhibited inflammatory cytokines IL-6 and TNF-alpha production in macrophages. These data suggest that sirolimus may prevent cellular cholesterol accumulation even in the presence of hyperlipidemia and inflammation, by regulating both cholesterol homeostasis and inflammatory responses.
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PMID:Effects of sirolimus on mesangial cell cholesterol homeostasis: a novel mechanism for its action against lipid-mediated injury in renal allografts. 1576 38


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