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)

The ability of the vasculature to modify its geometry in accordance with conditions of its microenvironment--the process of vascular remodeling--is an important pathobiologic process common to vascular disorders such as atherosclerosis, restenosis after angioplasty, and hypertension. Vascular remodeling characterizes the natural history of atherosclerosis, contributes to increased vascular resistance, and may contribute to the clinical complications of hypertension. A growing body of evidence indicates that locally generated vasoactive substances such as angiotensin II and nitric oxide are important determinants of the natural history of vascular disease. In particular, angiotensin II may promote vascular lesion formation by increasing vascular cell population via increased cell growth and decreased programmed cell death, and it may also alter extracellular matrix composition. Thus, angiotensin II is a pleiotropic local mediator capable of modulating cell growth, programmed cell death, migration of vascular smooth muscle cells, and extracellular matrix modulation, all of which are biologic mechanisms of vascular remodeling and intimal formation. This is proposed to occur via a local tissue angiotensin system. Angiotensin II may also promote chronic hypertension by modulating the vascular redox state and promoting the catabolism of the endothelium-derived nitric oxide, an endogenous inhibitory vasodilator. Because angiotensin-converting enzyme (ACE) is strategically positioned to influence the activity of at least three local vasoactive systems--angiotensin II, nitric oxide, and bradykinin--blocking ACE with ACE inhibition may have profound effects on ventricular and vascular structure and function, and have particular efficacy in preventing the morbidity and mortality of vascular diseases such as hypertension and atherosclerosis.
 ...
PMID:Vasculoprotective and cardioprotective mechanisms of angiotensin-converting enzyme inhibition: the homeostatic balance between angiotensin II and nitric oxide. 942 48

The Authors report, in this article, about pathophysiology mechanism that is to the base of the vascular injury mediate from the Angiotensin II able of modulate the primer, the acceleration and the progression of the atherosclerosis. Afterward is considered the importance of the administration of the inhibiting of the receptors AT-1 (Losartan) in the control of the hypertension and of the atherosclerosis.
 ...
PMID:[Physiopathology of angiotensin II and vascular lesion]. 949 56

Angiotensin II (AII) receptor type 1 (AT1), a G-protein-coupled receptor, is involved in the development of cardiovascular diseases such as hypertensin, cardiac hypertrophy, and atherosclerosis. Recent reports indicate that tyrosine phosphorylation of multiple intracellular molecules is responsible for most of these AII actions mediated by AT1, similar to receptor tyrosine kinase signaling pathways. AII activates MAPK by tyrosine phosphorylating the EGF receptor by the mechanism called transactivation with subsequent Ras activation in vascular smooth muscle and cardiac fibroblast cells. In contrast, AT1 leads to MAPK activation through PKC in cardiac myocytes. In addition to these signals, JAK/STAT pathways, which mediate cytokine actions, are also important for several AII functions through AT1.
 ...
PMID:[Intracellular signaling pathways of angiotensin II receptor type 1 involved in the development of cardiovascular diseases]. 970 74

Angiotensin-converting enzyme (ACE) inhibitors have shown unexpected benefits in the prevention of ischemic events in patients with hypertension and congestive heart failure. In addition to these clinical observations, there is a growing body of knowledge about the molecular and cellular effects of ACE inhibitors. For example, ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions. Angiotensin II blockade also diminishes the production of superoxide anion, which inactivates ambient nitric oxide. ACE inhibition of kininase II inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level within the vasculature, ACE inhibition shifts the balance of ongoing mechanisms in favor of those promoting vasodilatory, antiaggregatory, antithrombotic, and antiproliferative effects. These effects underlie the potential benefits of ACE inhibition in the therapy of ischemia and atherosclerosis. Some data is available in humans to show that these effects can be sustained for months, thereby maintaining improved endothelial function and, presumably, allowing the initiation of steps that might alter the progression of atherosclerosis. Definitive information is not yet available in humans to show that ACE inhibition clearly alters the progression of atherosclerosis or diminishes coronary events in uncomplicated coronary disease. This promising area of investigation is, however, the subject of multiple clinical trials, which should provide clarification of this important question in coming years.
 ...
PMID:Role of angiotensin-converting enzyme inhibition in reversal of endothelial dysfunction in coronary artery disease. 970 67

Angiotensin II (Ang II) promotes vascular smooth muscle growth and may be involved in the initiation and progression of atherosclerosis. To examine whether Ang II receptor expression in vascular tissues is altered in atherosclerosis, male New Zealand White rabbits were fed a high-cholesterol diet (1% cholesterol + 4% coconut oil mixed with regular chow; hypercholesterolemic group, n=12) or regular chow (control group, n=8) for 10 weeks. At the end of this period, the serum cholesterol level in the rabbits fed the high-cholesterol diet was higher than that in the control group (3616 +/- 144 versus 30 +/- 1 mg/dL, P<0.001). There was no atherosclerosis in the aortas of the control group, whereas 51 +/- 6% of the aorta was covered with atherosclerosis in the hypercholesterolemic group. Total Ang II receptor expression in the atherosclerotic aortic tissues was increased 5-fold in the hypercholesterolemic rabbits (292 +/- 28 versus 51 +/- 32 fmol/mg tissue, mean +/- SE, P<0.001), and the increased Ang II receptor expression was entirely due to enhanced Ang II type 1 (AT1) receptor expression (289 +/- 38 versus 38 +/- 18 fmol/mg, P<0.001), as Ang II type 2 receptor expression was unaltered (7 +/- 5 versus 3 +/- 2 fmol/mg, P=NS). AT1 receptors were localized primarily in the media and to some extent in the intima of the atherosclerotic aorta, as determined by immunohistochemistry with specific monoclonal and polyclonal AT1 receptor antibodies. Increased synthesis of AT1 receptor mRNA in atherosclerotic tissues was confirmed by reverse transcription-polymerase chain reaction. To evaluate the functional significance of increased AT1 receptor expression, the constrictor response of aortic rings to Ang II was examined and found to be markedly enhanced in atherosclerotic aortic rings (P<0.01 versus control aortic rings). The endothelium-dependent relaxation of aortic rings from hypercholesterolemic rabbits was markedly attenuated (P<0.001). This study shows that hypercholesterolemia in rabbits results in atherosclerosis, loss of endothelium-dependent relaxation, and increased Ang II receptor (entirely AT1 receptor) expression in aortic tissues, which may result in altered vasoreactivity.
 ...
PMID:Increased angiotensin II type 1 receptor expression in hypercholesterolemic atherosclerosis in rabbits. 974 32

Cell-surface expression of endothelial P-selectin increases adhesion and migration of leukocytes and thus may participate in the pathogenesis of reperfusion injury and atherosclerosis. Angiotensin II (Ang II) is also thought to be involved in such disease states. Nitric oxide (NO) downregulates P-selectin expression, and bradykinin (BK) is known to stimulate NO release from endothelial cells. The objective of this study was to determine the effects of 10-min stimulation of cultured human umbilical endothelial cells (HUVECs) with Ang II, BK, or both on P-selectin expression. Ang II (10(-9)-10(-5) M) stimulated P-selectin expression in a concentration-dependent manner, exhibiting a significant effect at 10(-7) M and reaching a plateau at 5 x 10(-5) M. Pretreatment of HUVECs with the AT1 antagonist losartan and the AT1/AT2 antagonist saralasin but not the AT2 antagonist PD123319 (all at 10(-5) M) markedly attenuated the effect of 10(-7) M Ang II. The effects of Ang II on P-selectin expression were not affected by the presence of the NO synthase inhibitor nitro-L-arginine (L-NA, 5 x 10(-4) M) but were abolished by pretreatment with superoxide dismutase (SOD). BK (10(-6) M) abolished the effects of 10(-7) M Ang II on P-selectin expression but did not affect P-selectin expression induced by desmopressin (0.01-10 microM). L-NA obliterated the blunting effect of BK on the Ang II-induced P-selectin membrane expression. BK alone slightly stimulated P-selectin expression, but in the presence of L-NA, BK markedly enhanced P-selectin expression. The effects of BK in the presence of NA were not altered by SOD, indicating that at difference with Ang II, it acts by a mechanism other than superoxide generation. Thus, Ang II acting on AT1 receptors stimulates superoxide generation, which, in turn, induces expression of P-selectin on the endothelial cell surface. BK inhibits the effects of Ang II, likely acting via NO. We conclude that the balance between Ang II, BK, and NO can regulate P-selectin expression on the endothelial cell membrane, an important component of the cascade leading to leukocyte adhesion to the vascular endothelium.
 ...
PMID:Angiotensin II and bradykinin regulate the expression of P-selectin on the surface of endothelial cells in culture. 975 92

The vascular renin-angiotensin system (RAS) is regulated independently from circulating RAS and plays a role in the local regulation of vascular tone, the modulation of sympathetic activity and vascular remodeling. Endothelial cells are a major source of angiotensin converting enzyme (ACE), which produces angiotensin II and degrades bradykinin, in normal arteries. Mechanical stress such as transmural pressure, stretch stress and shear stress appear to contribute to the regulation of endothelial ACE activity. In contrast, vessels with intimal proliferation such as atheromatous plaque and neointima following balloon injury show expression of ACE in smooth muscle cells and macrophages in the intimal lesions. Activation of ACE in intimal SMC may relate to a phenotypic change of SMC from the contracting type of the synthetic type. Activation of ACE in macrophages is also related to the transformation of macrophages from monocytes. Concerning the role of the activated RAS, elevated blood pressure and vascular tonus by angiotensin II are candidates of vascular injury and plaque rupture. Angiotensin II stimulates migration and proliferation of smooth muscle cells and production of extracellular matrix. Furthermore, angiotensin II increases oxidized-LDL which may be related to the forming of macrophages. These evidence suggest that activation of vascular RAS following endothelial dysfunction/injury play an important role in the pathogenesis of vascular remodeling and atherosclerosis.
 ...
PMID:[Vascular endothelial cells and renin-angiotensin system]. 986 99

Angiotensin II (Ang II) promotes vascular smooth muscle cell (VSMC) growth and migration, but the signaling pathways mediating these VSMC behaviors critical to restenosis and atherosclerosis are not completely known. The purpose of the present investigation was to define the role of mitogen-activated protein kinase (MAPK) in Ang II-induced DNA synthesis, migration, and c-fos induction in VSMCs. PD 98059, a synthetic inhibitor of MAPK kinase, or antisense oligodeoxynucleotides (ODNs) to deplete extracellular signal-regulated kinase (ERK)1 and ERK2 MAPKs, were used to inhibit MAPK signaling. PD 98059 at 30 micromol/L reduced Ang II-induced MAPK activity by 69% (P<0.01). Under these conditions, Ang II-induced DNA synthesis was completely inhibited (P<0.01), and Ang II-directed migration was attenuated by 76% (P<0.05). In contrast, induction of c-fos by Ang II was only partially suppressed (58% inhibition, P<0.01). Antisense ODNs against the initiation site of rat ERK1 and ERK2 MAPK mRNAs reduced corresponding protein levels by 63% (P<0.01) and completely inhibited MAPK activation by either Ang II (1 micromol/L) or 10% serum. Antisense ODNs (0.4 micromol/L) completely inhibited Ang II-induced DNA synthesis (P<0.01), decreased migration by 47% (P<0.01), and reduced c-fos induction by 40% (P<0.01 versus control ODN-transfected VSMCs). The Ang II type 1 (AT1)-receptor blocker irbesartan completely blocked DNA synthesis, migration, MAPK activation, and c-fos induction by Ang II in VSMCs. These results demonstrate that activation of MAPK plays a crucial role in Ang II-directed migration and DNA synthesis through the AT1 receptor. In contrast, Ang II-mediated c-fos induction and migration were only partially inhibited by either antisense ODNs or PD 98059, suggesting that other pathways in addition to the MAPK pathway may be involved in these actions of Ang II. We conclude that MAPK is a critical regulatory factor for Ang II-mediated migration and growth in VSMCs. Ang II-induced DNA synthesis showed a stronger MAPK dependence than did Ang II-directed migration or c-fos induction.
 ...
PMID:Central role of the MAPK pathway in ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells. 988 69

Our previous experiments demonstrated upregulation of the renin-angiotensin system in macrophages, including angiotensin II type 1 (AT1) and type 2 (AT2) receptors, during transformation from monocytes. We investigated the role of angiotensin II in oxidative stress of monocytes/macrophages, which plays a role in the advance of atherosclerosis. THP1, a human monocytic leukemia cell line, was differentiated to macrophages by adding of phorbol 12-myristate 13-acetate for 24 hours. The intracellular production of peroxide was measured by a cytofluorometric assay with 2', 7'-dichlorofluorescein-diacetate with a flow cytometer scan. Peroxide was detected in monocytes and upregulated during the transformation to macrophages by 3.18+/-0.52 times in relative fluorescein of peak value (P<0.01). Angiotensin II (1 micromol/L) induced oxidative stress in macrophages, with the peak at 15 minutes by 451+/-223%, and returned to the control level within 1 hour. EC50 was 5.4x10(-9) mol/L. AT1 antagonist (CV11974, 1 micromol/L) significantly decreased angiotensin II-induced oxidative stress in macrophages, but AT2 antagonist (PD123319, 1 micromol/L) did not. Of interest, AT1 antagonist also decreased basal levels of peroxide production in macrophages in a dose-dependent manner. These results suggest that upregulation of the expression of AT1 receptor in macrophages contributes in part to upregulation of peroxide production. AT1 receptor antagonists may be useful to suppress oxidative stress of macrophages in atherosclerotic lesions.
 ...
PMID:Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. 993 Nov 26

Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappaB in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappaB, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappaB. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.
 ...
PMID:Angiotensin induces inflammatory activation of human vascular smooth muscle cells. 1039 79


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