Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence to suggest that elevated plasma levels of lipoprotein (a) [Lp(a)] represent a risk factor for the development of atherosclerotic vascular disease, but the mechanism by which this lipoprotein localizes to involved vessels is only partially understood. In view of studies suggesting a link between inflammation and atherosclerosis and our previous finding that leukocyte defensin modulates the interaction of plasminogen and tissue-type plasminogen activator with cultured human endothelial cells, we examined the effect of this peptide on the binding of Lp(a) to cultured vascular endothelium and vascular smooth muscle cells. Defensin increased the binding of Lp(a) to endothelial cells approximately fourfold and to smooth muscle cells approximately sixfold. Defensin caused a comparable increase in the amount of Lp(a) internalized by each cell type, but Lp(a) internalized as a consequence of defensin being present was not degraded, resulting in a marked increase in the total amount of cell-associated lipoprotein. Abundant defensin was found in endothelium and in intimal smooth muscle cells of atherosclerotic human cerebral arteries, regions also invested with Lp(a). These studies suggest that defensin released from activated or senescent neutrophils may contribute to the localization and persistence of Lp(a) in human vessels and thereby predispose to the development of atherosclerosis.
 ...
PMID:Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells. 919 51

The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.
 ...
PMID:Thrombosis and atherosclerosis. 933 57

Blood vessels affect the quality of life in many ways. They provide an essential nutritive function during growth and repair of tissues but, on the other hand, can become affected by disorders or trauma, resulting in bleeding, thrombosis, arterial stenosis, and atherosclerosis. Three molecular systems, the vascular endothelial growth factor (VEGF) system, the plasminogen system, and the coagulation system, have been implicated in the formation and pathobiology of blood vessels. This review focuses on the role of these systems in these processes. Recent gene-targeting studies have identified VEGF as a potent modulator of the formation of endothelial cell-lined channels. Somewhat unanticipated, the initiator of coagulation is not only involved in the control of hemostasis but also in the maturation of a muscular wall around the endothelium. With different murine models of cardiovascular disease, a pleiotropic role of the plasminogen system was elucidated in thrombosis, in arterial neointima formation after vascular wound healing and allograft transplantation, in atherosclerosis, and in the formation of atherosclerotic aneurysms. Surprisingly, tissue-type plasminogen activator is also involved in brain damage after ischemic or neurotoxic insults. The insights from these gene-targeting studies have formed the basis for designing gene therapy strategies for restenosis and thrombosis, which have been successfully tested in these knockout models.
 ...
PMID:Molecular analysis of blood vessel formation and disease. 937 41

Hyperhomocysteinemia is associated with severe, premature atherosclerosis and thromboembolism. The mechanisms involved in the atherogenic and thrombotic complications of hyperhomocysteinemia are not understood. It has been suggested that hyperhomocysteinemia predisposes to atherosclerosis by injuring the vascular endothelium. Whether hyperhomocysteinemia is independently associated with changed endothelial function, either in the absence or the presence of clinically manifest atherosclerotic disease, is, however, not known. Therefore we investigated, both in patients with peripheral arterial occlusive disease and in healthy individuals, whether plasma protein markers of endothelial function differed between subjects with, and subjects without hyperhomocysteinemia. We studied 80 individuals under the age of 56 years: healthy individuals with (n = 20) and without (n = 20) hyperhomocysteinemia and patients with peripheral arterial occlusive disease with (n = 20) and without (n = 20) hyperhomocysteinemia. The following endothelium-derived proteins were measured as markers of endothelial cell function: von Willebrand factor (vWf) and von Willebrand factor propeptide (vWf: AgII), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), cellular fibronectin (cFN) and thrombomodulin (TM). In addition we assessed C-reactive protein (CRP). vWf, vWf: AgII, tPA and CRP were significantly higher in the patients with peripheral arterial occlusive disease than in the healthy individuals. No differences in marker protein plasma levels were found between individuals with, and those without hyperhomocysteinemia, apart from vWf, which was significantly raised in hyperhomocysteinemic as compared to normohomocysteinemic patients. We did not find any evidence for an independent association between hyperhomocysteinemia and protein markers of endothelial cell function in healthy subjects.
 ...
PMID:Endothelial marker proteins in hyperhomocysteinemia. 940 14

The urokinase-type plasminogen activator (UPA) and its receptor are expressed in the vasculature and are involved in cell migration and remodeling of the extracellular matrix in the neointima. Vessels with atherosclerosis or neointimal hyperplasia, when compared with normal vessels, contain high UPA activity as well as increased levels of UPA receptor. In this study, we have identified the stimulation of vascular smooth muscle cell proliferation as a novel activity for UPA in the vessel wall. High-molecular-weight-UPA (12-200 nmol/L range) stimulated DNA synthesis and cell proliferation, which was half that induced by fetal calf serum or by platelet-derived growth factor-BB. UPA did not induce growth of endothelial cells, and tissue-type plasminogen activator showed no activity on either cell type. Induction of proliferation required the complete UPA molecule but was independent of the proteolytic activity of UPA, whereas neither the amino-terminal fragment nor the catalytic domain by itself was mitogenic. UPA also stimulated c-fos/c-myc mRNA expression and mitogen-activated protein kinase activity in smooth muscle cells. Blocking monoclonal antibodies against the UPA receptor and the enzymatic removal of receptors were ineffective in inhibiting the mitogenic effect of UPA, suggesting a UPA receptor-independent mechanism. Thus, we provide evidence for a novel function of UPA on vascular smooth muscle cell proliferation that, together with its previously documented involvement in regulating pericellular proteolysis-related events and cell migration, provides additional evidence for a role in the pathogenesis of atherosclerosis/restenosis.
 ...
PMID:Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders. 940 65

Plasminogen activators (PAs) and their inhibitor, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in modulation of luminal fibrinolysis and mural proteolysis contributing to atherogenesis. Expression of PAs/PAI-1 (normalized to extracted tissue protein) was delineated by assays of conditioned media and of extracts from walls of human arterial segments in culture. Arterial specimens (n = 39 from 26 subjects) were divided into four groups: normal (n = 14), fatty streak (n = 6), moderate atherosclerosis (mural thickening with < 70% lumen obstruction, n = 5), and severe atherosclerosis (mural thickening with > 70% lumen obstruction, n = 14). Paired samples from the same individual comprising a normal arterial segment and an atherosclerotic segment were evaluated also. A fourfold molar excess in PAI-1:t-PA was seen in conditioned media from samples with any evidence of atherosclerosis compared with normal specimens (normal 21 +/- 4, diseased 82 +/- 21, P < or = .05). Compared with normal pairs, the tissue content of PAI-1 (ng) was increased in fatty streak lesions (n = 3, normal 35 +/- 12, fatty streak 50 +/- 8, P < or = .05); stable to decreased in moderate atherosclerosis (n = 3, normal 34 +/- 3, moderate 22 +/- 7, P = .16); and increased in severe atherosclerosis (n = 6, normal 48 +/- 9, severe 85 +/- 19, P < or = .05). The tissue content of PAs (ng), though not increased in fatty streak lesions, was elevated in moderately and severely atherosclerotic segments (normal 0.7 +/- 0.2, moderate 1.6 +/- 0.1; normal 0.8 +/- 0.3, severe 2.1 +/- 0.3, P < or = .05 for each comparison). Atherogenesis is associated with decreased luminal fibrinolytic capacity that may exacerbate thrombosis. Decreased mural proteolysis in early atherogenesis may exacerbate matrix accumulation. Increased mural proteolysis later is associated with, and may potentiate, smooth muscle cell migration and proliferation.
 ...
PMID:Changes in arterial expression of fibrinolytic system proteins in atherogenesis. 940 25

A study made to gain insight into the bodily immune and fibrinolytic systems in 72 patients with cardiac insufficiency developed against the background of cardial atherosclerosis showed imbalance in the ratio of cellular to humoral links of immunity and enhancement of the autoimmune processed activity, inhibition of activity of the monocytomacrophagal link. Disturbances in the fibrinolytic system were manifested by blood and urine lowering of activity of the plasminogen activator, with the antiplasmin activity being on the decrease as well, which fact is regarded as formation of a new stationary state in the system of haemocoagulation maintaining hemostasis.
 ...
PMID:[The immune and fibrinolytic systems in heart failure developing against a background of cardiac atherosclerosis]. 947 78

Sudden extreme physical stress is associated with an increased risk of myocardial infarction mainly in people with preexisting atherosclerosis. In this study we compared the effect of submaximal exercise on coagulation and fibrinolysis in patients with peripheral arterial occlusive disease (PAOD) with that in healthy control subjects. Fifteen PAOD) patients with intermittent claudication and 15 healthy control subjects, matched for age, sex, medication use, smoking habit, and conditioning, were studied. Thrombin-antithrombin III complex (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 antigens (Ag), t-PA activity, and plasmin-alpha2-antiplasmin complex (PAP), as well as plasma catecholamines, were measured before and after a treadmill exercise test. At rest, fibrinogen (3.3+/-0.5 versus 2.9+/-0.5 g/L [mean+/-SD]; P<.05), D-dimer (392+/-128 versus 271+/-113 ng/mL; P<.05), t-PA Ag (9.1+/-5.1 versus 5.5+/-1.2 ng/mL; P<.02), and PAI-1 Ag (14.9+/-7.1 versus 7.6+/-3.8 ng/mL; P<.002) levels in plasma were markedly higher in the patient group than in the control group. In patients but not in control subjects, exercise of similar intensity elevated circulating concentrations of TAT (from 3.43+/-1.45 to 4.83+/-2.27 ng/mL; P<.05). Exercise caused a parallel increase in D-dimer, t-PA Ag, t-PA activity, PAP, and catecholamines in both groups, whereas PAI-1 Ag remained stable. Plasma lactic acid was significantly higher in patients after exercise and was associated with lower-limb ischemia. Compared with healthy control subjects, patients with PAOD showed higher t-PA Ag, PAI-1 Ag, and D-dimer levels both at rest and after exercise. Notably, submaximal exercise on a treadmill enhanced thrombin formation in patients with PAOD but not in the control subjects. Sudden catecholamine release and local ischemia during exercise may accelerate the preexisting prothrombotic potential of the atherosclerotic vessel wall.
 ...
PMID:Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. 948 89

Statins are most potent lipid-lowering drugs. The mechanisms of their action is specific inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity. HMG-CoA reductase catalyses the reduction of HMG-CoA o mevalonate and is rate-limiting step in cholesterol biosynthesis pathway. Mevalonate is considered to be not only an important intermediate of cholesterol synthesis, but also the source of isoprenoids which play important role in DNA replication and cell growth. It was shown that statins inhibit the proliferation and migration of vascular smooth muscle cell--key events in atherogenesis. HMG-CoA reductase inhibitors lower the reactivity of arterial wall to vasoconstrictor agents, decrease the concentration of lipoprotein [a]--an independent risk factor of atherosclerosis, inhibit the generation of free radicals and lipid peroxidation, decrease the number of macrophages in atherosclerotic lesion and finally, equilibrate the clotting-fibrynolysis processes of attennuating platelets function, reducing the tissue factor synthesis and decreasing the concentration of plasminogen activator inhibitors. Statins are presently considered by NCEP to be the drugs of first choice for treatment of hypercholesterolemia.
 ...
PMID:[Anti-atherosclerotic actions of HMG-CoA reductase inhibitors]. 950 89

Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation of coagulatory and anticoagulatory factors by endothelial cells contributes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable conditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivalents and was 0.78+/-0.14 nM MDA/mg LDL for native LDL and 13.63+/-1.18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-1 activity were higher in macrovascular endothelial cells. Incubation of n-LDL in concentrations ranging from 3 to 100 microM/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in both cell types. Ox-LDL (3 to 100 microM/ml LDL protein) decreased t-PA secretion in a concentration dependent manner from 30.9+/-1.7 to 13.7+/-30 ng/ml per 24 h per 10(6) cells (P < 0.01), increased PAI-1 antigen from 2772+/-587 to 4441+/-766 ng/ml per 24 h per 10(6) cells (P < 0.05) as well as PAI-1 activity from 34+/-6 to 55+/-9 AU/ml per 24 h per 10(6) cells (P < 0.05) in macrovascular endothelial cells but had only minor effects on microvascular endothelial cells. Procoagulant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197+/-6 to 76+/-6 s/24 h per 10(6) cells (P < 0.05). The effect on PAI-1 secretion showed a dependency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE), which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macrovascular endothelial cells to ox-LDL may partially determine the localization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients.
Atherosclerosis 1998 Mar
PMID:Human cardiac microvascular and macrovascular endothelial cells respond differently to oxidatively modified LDL. 956 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>