Angiogenesis: A link to Thrombosis in Athero-thrombotic Disease

Conway, Edward M.

doi:10.1159/000083809

Cited by 17 publications

(18 citation statements)

References 47 publications

(42 reference statements)

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“…Moreover, the UPS degrades many molecules and regulators of apoptosis and angiogenesis, 3 crucial mechanisms of plaque formation and rupture. 9,10 It is therefore conceivable that dysregulation of the UPS plays a role in atherosclerotic plaque progression and tendency to rupture. Indeed, increased expression of ubiquitin conjugates has been demonstrated in human coronary plaque responsible for lethal myocardial infarction as compared with noninfarct related coronary lesions.…”

mentioning

confidence: 99%

Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Versari

Herrmann

Gössl

et al. 2006

ATVB

107

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Objective-The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation. Key Words: atherosclerosis Ⅲ carotid plaque Ⅲ endarterectomy Ⅲ oxidative stress Ⅲ proteasome Ⅲ stroke Ⅲ ubiquitin T he ubiquitin-proteasome system (UPS) is responsible for the nonlysosomal degradation of the majority of intracellular proteins, 1,2 thus playing a crucial role in the regulation of many cellular processes. 3 The process of ubiquitination requires various enzymatic activities, involving specific proteins, ie, E1, E2, E3, which activate and transfer polyubiquitin chains to target proteins, leading eventually to the formation of a complex which is recognized and degraded by the 26S proteasome complex. 4 This complex is composed of a 20S core particle that embodies the catalytic activity and 2 19S regulatory particles. The targets of the UPS include key regulators of cell cycle and apoptosis and various transcription factors, whose intracellular levels are finely tuned in the maintenance of the optimum equilibrium for cell division, growth, differentiation, signal transduction, and response to stress. 3,5 Many of these processes are crucially involved in the onset, progression, and complication of atherosclerosis. In particular the UPS plays a key role in the activation of NF-B, 6 which has been associated with coronary 7 and carotid 8 plaque instability. Moreover, the UPS degrades many molecules and regulators of apoptosis and angiogenesis, 3 crucial mechanisms of plaque formation and rupture. 9,10 It is therefore conceivable that dysregulation of the UPS plays a role in atherosclerotic plaque progression and tendency to rupture. Indeed, increased expression of ubiquitin conjugates has been demonstrated in human coronary plaque responsible for lethal myocardial infarction as compared with noninfarct related coronary lesions. 11 See coverA high rate of protein ubiquitination is associated with increased oxidative stress 12 especially in neurological disorders [13][14][15] and UPS has been demonstrated to be the principal system responsible for the degradation of oxidized proteins. 16 However, high-level oxidative stress can also impair UPS by reducing proteasome activity. 15,17 This could lead to intracellular accumulation of ubiquitinated substrates caused by an increased production and by a reduced degradation. As shown in the development of cataract, 18 intracellular ubiquitinated damaged proteins may eventually accumulate, form aggre-

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mentioning

confidence: 99%

Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Versari

Herrmann

Gössl

et al. 2006

ATVB

107

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“…7,[22][23] Furthermore, hypoxia stabilizes HIFs and leads to the accumulation of ado. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] This study reports, for the first time, that ado increases HIF-1␣ protein levels in U937, HMs, and FCs in hypoxia as already observed in cancer cells. 19,[25][26] A 2B and A 3 subtypes play a major role in the VEGF increase and FC formation and only the A 2B is responsible for IL-8 stimulation induced by adenosine.…”

Section: Discussionmentioning

confidence: 83%

“…9 It has been also demonstrated that in vascular endothelium, under hypoxia, IL-8 expression is increased by HIF. 10,11 However, the relationships between HIF and IL-8 has been questioned by other authors. 12 Adenosine (Ado) is a proangiogenic purine nucleoside released from ischemic and hypoxic tissues.…”

mentioning

confidence: 99%

Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Gessi

Fogli

Sacchetto

et al. 2010

ATVB

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Objective-Foam cell (FC) formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and FC development. M acrophage foam cell formation is an important process in atherosclerotic plaque development. 1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesionprone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called "foam cells" (FCs), which in turn give rise to fatty streaks in the arterial wall. 2 As the atherosclerotic lesion develops, the arterial wall thickness increases and oxygen diffusion into the intima is markedly reduced. These hypoxic regions contain large number of FCs revealing that these cells experience hypoxia during the development of atherosclerotic lesions. 3-4 Hypoxia-inducible factor-1 (HIF-1), the most important factor involved in the cellular response to hypoxia, is a heterodimeric transcription factor composed of an inducibly expressed HIF-1␣ subunit and a constitutively-expressed HIF-1␤ subunit. 5 It is well established that HIF plays a major role in vascular endothelial growth factor (VEGF) expression and angiogenesis, mediating important alterations associated with atherogenesis and angiogenic activity of macrophages. 6 -7 Moreover, under atherogenic conditions, the high expression of HIF-1 in macrophages promotes FC formation and atherosclerosis. 8

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“…Thrombosis plays a critical role in the pathomechanism of ischemic syndromes, as disruption of an atherosclerotic plaque exposes blood to subendothelial collagen, tissue factor, and other procoagulant molecules such as thrombin that trigger activation of platelets and formation of fibrin within the vessel lumen (14)(15)(16). Endothelial damage and dysfunction as well as inflammation and coagulation are closely related to the pathophysiology of ischemic syndromes (17).…”

Section: Atherothrombosis and Ischemiamentioning

confidence: 99%

Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease

Jacomella

Corti

Husmann

2013

Current Opinion in Pharmacology

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Anticoagulant and antiplatelet drugs are used and studied in numerous trials for primary and secondary prevention of atherothrombosis since decades. The annual rate for cardiovascular morbidity and mortality is high in patients following an acute coronary syndrome and in patients with peripheral arterial disease (PAD) due to concomitant cardiac and cerebrovascular diseases. Plaque rupture and subsequent thrombosis involves activation of both platelets and coagulation factors. Therefore the combination of aspirin and warfarin to improve prevention of atherothrombosis compared to antiplatelet therapy alone was studied but could not be established due to significantly increased risk of major bleeding compared to a nonsignificant reduction in ischemic events. During the past two decades, clinical trials focused on combined antiplatelet therapies for the prevention of secondary events following acute coronary syndromes and very recently on the new oral anticoagulants in combination with antiplatelet therapy. This review discusses the role of the new oral anticoagulants such as Factor IIa (thrombin) and Factor Xa inhibitors in atherothrombosis, their pharmacological properties and recently published clinical data in secondary prevention of atherothrombotic events and potential implications for patients with PAD.

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Angiogenesis: A link to Thrombosis in Athero-thrombotic Disease

Cited by 17 publications

References 47 publications

Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease

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