Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoporosis is associated with both atherosclerosis and vascular calcification. No mechanism yet explains the parallel progression of these diseases. Here, we demonstrate that osteoclasts (OCL) depend on lipoproteins to modulate cellular cholesterol levels and that this controls OCL formation and survival. Removal of cholesterol in OCL via high-density lipoprotein or cyclodextrin treatment dose-dependently induced apoptosis, with actin disruption, nuclear condensation and caspase-3 activation. One mechanism linked to the induction of OCL apoptosis was the cell-type-specific failure to induce HMG-CoA reductase mRNA expression, suggesting an absence of feedback regulation of de novo cholesterol biosynthesis. Furthermore, cyclodextrin treatment substantially suppressed essential M-CSF and RANKL-induced survival signaling pathways via Akt, mTOR and S6K. Consistent with these findings, cholesterol delivery via low-density lipoprotein (LDL) significantly increased OCL viability. Interestingly, OCLs from the LDL receptor (LDLR)-/- mouse exhibited reduced size and lifespan in vitro. Remarkably, LDLR+/+ OCL in lipoprotein-deficient medium phenocopied LDLR-/- OCL, while fusion and spreading of LDLR-/- OCL was rescued when cholesterol was chemically delivered during differentiation. With hyperlipidemia being associated with disease of the vascular system and bone, these findings provide novel insights into the selective lipoprotein and cholesterol dependency of the bone resorbing cell. Cell Death and Differentiation (2004) 11, S108-S118. doi:10.1038/sj.cdd.4401399 Published online 12 March 2004
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PMID:Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins. 1524 77

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
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PMID:AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. 1661 76

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.
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PMID:Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. 1681 51

Cancer and vascular diseases remain the predominant causes of morbidity and mortality in industrialized countries worldwide. The course of atherosclerosis with initiation, progression, and complication parallels the three stages of carcinogenesis with induction, growth, and invasion of tissue and neoangiogenesis. Within this framework, the oncogene c-Myc and growth factors pathways are acquiring increasing importance. Insulin-like growth factor-1 (IGF-1) pathway emerges among them for its versatile pleiotropic actions. A number of genes that permit extensive communication between IGF-1-AKT, p53, and mammalian target of rapamycin (mTOR) pathways have been identified. In turn these pathways lead to p53 transcriptional program, the forkhead transcriptional programs, autophagy, and translational controls, which determine cell growth or arrest, cell survival or death. The increased understanding of the extensive communication and coordination between all these pathways may enable to targeting these events and to prevent neoplastic and vascular diseases. Great effort has been focused on the development of new agents designed to target various steps of c-Myc, Ras, and IGF cascade. However, what have we recently learned about their safety and effectiveness? Here, we review the very recent advances in the identification of novel inhibitors as well as antisense oligonuleotides (ASOs) and siRNA that are proving their usefulness in ongoing clinical trials both in terms of toxicity and specificity.
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PMID:Targeting c-Myc, Ras and IGF cascade to treat cancer and vascular disorders. 1692 Dec 63

Allograft vasculopathy remains the nemesis of long-term survival in heart transplantation. Possible modifying risk factors such as obesity, diabetes, and hypertension should continue to be pursued aggressively. All patients should receive statins. Clinical trials will provide the evidence needed to ascertain whether mammalian target of rapamycin inhibitors should be used in de novo cardiac transplant recipients to attenuate cardiac allograft vasculopathy (CAV). Intravascular ultrasound appears to play a key role in the diagnosis and evaluation of new treatments, and may indeed represent a surrogate marker that can be used to tailor management and improve outcomes. A better understanding of CAV is needed to develop targeted preventive therapies. Ongoing research in native atherosclerosis and vascular biology may provide answers within the next decade.
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PMID:Cardiac allograft vasculopathy: an update. 1754 12

Interferon (IFN)-gamma, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.
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PMID:Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation. 1787 72

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.
Atherosclerosis 2008 May
PMID:Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia. 1798 Mar 69

Mammalian target of rapamycin (mTOR) integrates nutrient and hormonal signals involved in cell growth. Development of mTOR inhibitor drugs as therapeutic agents for major human diseases such as obesity, diabetes, atherosclerosis, or cancer will experience an important increase in the next years. The incidence of these diseases is particularly increased among organ transplant recipients being a limiting factor for transplant success. Transplant teams carry on significant experience in treating patients with mTOR inhibitors for preventing acute rejection or reducing nephrotoxicity. Preliminary data showed that these drugs are effective for reducing posttransplant malignancy. Transplant teams have the unique opportunity to analyze whether mTOR inhibitors are also effective for the prevention of cardiovascular diseases, obesity, and diabetes.
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PMID:Nonimmunosuppressive effects of mammalian target of rapamycin inhibitors. 1863 60

Monocytes/macrophages recruited into the arterial wall during atherogenesis are crucial in the initiation and progression of atherosclerosis and play a fundamental role in the destabilization process that is the main causal event of acute coronary syndromes. In the present study, we investigated the effect of the mammalian target of rapamycin inhibitor everolimus on macrophage accumulation within carotid lesions elicited by perivascular collar placement in cholesterol-fed rabbits. Everolimus (1.5 mg/kg given 1 day before collaring followed by 1 mg/kg/day for 14 days, administered by oral gavage) markedly decreased lesion macrophage content as compared with vehicle control (-65%; p < 0.01). This effect was associated with a reduction in intimal thickening and occurred in the absence of changes in plasma cholesterol concentrations. To gain insights on the potential mechanism(s) underlying this effect, we investigated the influence of everolimus on chemoattractant-induced migration of human monocytes in vitro. Pretreatment with therapeutic concentrations of everolimus (10 nM) significantly lowered monocyte chemotaxis in response to various chemotactic factors (i.e., monocyte chemoattractant protein-1/CCL2, fractalkine/CX3CL1, interleukin-8/CXCL8, complement fragment 5a, or N-formyl-Met-Leu-Phe) without inducing monocyte cell death. These results suggest that everolimus may favorably influence the atherosclerotic process by affecting the recruitment of monocytes into early lesions.
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PMID:Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. 1902 42

Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-gamma inducible protein 10 (IP10) and MIG (monokine induced by interferon-gamma) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3(+) leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.
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PMID:Novel role of the CXC chemokine receptor 3 in inflammatory response to arterial injury: involvement of mTORC1. 2161 31


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