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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10(-7) M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P < 0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [3H]acetate into cholesterol) by up to 90% (P < 0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM's cholesterol synthesis by up to 70% (P < 0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10(-7) M Ang II for 18 h at 37 degrees C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10(-5) M), an AT1 blocker, but not PD 123319 (10(-5) M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.
Atherosclerosis 1999 Oct
PMID:Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. 1053 81

1. We have recently demonstrated that chronic infusion of Angiotensin II into apoE-/- mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co-infused Angiotensin II (1000 ng kg(-1) min(-1) for 28 days) with losartan (30 mg kg(-1) day(-1)) or PD123319 (3 mg kg(-1) day(-1)) to antagonize AT1 and AT2 receptors, respectively. 2. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE-/- mice. The formation of aortic aneurysms was totally inhibited by co-infusion of Angiotensin II with losartan (30 mg kg(-1) day(-1); P=0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3. To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE-/- mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology.
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PMID:Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. 1160 27

Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.
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PMID:Recent advances in angiotensin II signaling. 1221 72

Angiotensin II(AngII) activates NADH/NAPDH oxidase activity and stimulates reactive oxygen species(ROS) production, which induces many proinflammatory genes such as vascular cell adhesion molecule-1(VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1(MCP-1) mainly via AngII type I receptor(AT1). ROS are important in cardiovascular disease because many of these preinflammatory cytokines play a critical role in the initiation and progression of atherosclerosis. AT1 receptor blockade is important to prevent cardiovascular disease. AngII type 1 receptor blocker(ARB) and/or AngII converting enzyme inhibitor(ACEI) are useful for preventing cardiovascular disease. The role of AngII type II receptor(AT2) for producing ROS and/or cardiovascular damage has been studied.
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PMID:[Angiotensin II receptor and oxidative stress]. 1239 80

Since renin catalyses the first and rate-limiting step of the renin-angiotensin system (RAS) cascade, interruption of the generation of angiotensin II (Ang II) by renin inhibitors at this highly specific initial step of the cascade has long been a therapeutic goal. The early development of renin inhibitors was hampered by problems with bioavailability and high costs of synthesis. However, more recently a potent non-peptidic inhibitor of renin, aliskiren, with acceptable oral bioavailability, has been synthesised. Aliskiren effectively reduces Ang II levels in normal volunteers and has been shown to lower blood pressure (BP) in patients with mild-to-moderate hypertension. Renin inhibitors would be expected to have similar, but not identical effects to those of the established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of Ang II production may be more effective with renin inhibition than with angiotensin-converting enzyme (ACE) inhibition. Furthermore, because renin has high specificity for only one substrate, angiotensinogen, side-effects would be expected to be less frequent. It is currently unclear whether blockade of Ang II type 1 (AT1) receptors, leaving other Ang II receptors (AT2, AT3 and AT4) unblocked, is preferable to the reduction in plasma and tissue Ang II levels achieved with either ACE or renin inhibition. Pharmacological suppression of the RAS, through ACE inhibition, or blockade of AT1, beta-adrenoceptor or mineralocorticoid receptors, has been proven to reduce morbidity and mortality in patients with hypertension, diabetes mellitus, atherosclerosis, heart failure and nephropathy. While, to date, aliskiren has only been shown to reduce BP, it appears likely that orally-active renin inhibitors could prove useful in the management of a wide range of cardiovascular pathologies.
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PMID:Potential of renin inhibition in cardiovascular disease. 1269 47

Most of the deleterious effects of angiotensin II (Ang II) on blood pressure (BP), cardiovascular remodeling, and atherosclerosis are mediated by Ang II type 1 (AT1)-receptor activation. This explains why Ang-II-decreasing or blocking drugs have been successful in decreasing global cardiovascular morbimortality in patients with cardiac complications. However, in primary or secondary stroke prevention trials in patients with low cardiac risk, b-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazides and dihydropyridines, which increase Ang II. When compared with a beta-blocker, an Ang II-increasing AT1-receptor blocker better protects against stroke but not against cardiac events, whereas an ACEI gives the same protection against both cardiac and cerebral events. This dissociation between blood-pressure-independent cardiac and cerebral protection between b-blockers or ACEIs versus AT1-blockers in patients with low cardiac risk can be best explained if, besides the beneficial vascular effect of AT1-receptor blunting, there is evidence of a beneficial effect of non-AT1-receptor activation. In this review, we present experimental evidence for AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.
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PMID:Is the angiotensin II Type 2 receptor cerebroprotective? 1512 69

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-kappaB (NF-kappaB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-kappaB and upregulates some related proinflammatory genes. Our aim was to investigate whether other angiotensin-related peptides, as the N-terminal degradation peptide Ang IV, could regulate proinflammatory factors (activation of NF-kappaB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-kappaB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IkappaB degradation and induced NF-kappaB-dependent gene transcription. Ang II activates NF-kappaB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-kappaB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-kappaB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV-induced NF-kappaB activation and prevented IkappaB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-kappaB pathway via AT4 receptors. Ang IV also increased the expression of proinflammatory factors under NF-kappaB control, such as MCP-1, IL-6, TNF-alpha, ICAM-1, and PAI-1, which were blocked by the AT4 antagonist. Our results reveal that Ang IV, via AT4 receptors, activates NF-kappaB pathway and increases proinflammatory genes. These data indicate that Ang IV possesses proinflammatory properties, suggesting that this Ang degradation peptide could participate in the pathogenesis of cardiovascular diseases.
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PMID:Angiotensin IV activates the nuclear transcription factor-kappaB and related proinflammatory genes in vascular smooth muscle cells. 1583 14

Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in the development of micro- and macro-vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT1 receptors, whereas the AT2 receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT1 receptor blockers (ARBs) should provide additional end organ protection via AT2 receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs. Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT1 receptor blocker, or a hypothetical dual blocker of AT1 receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive clinical evidence to support the combined use of these drugs. This review highlights the available experimental data that support the therapeutic benefits of this combination.
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PMID:Saga of renin-angiotensin system and calcium channels in hypertensive diabetics: does it have a therapeutic edge? 1600 28

Discovery of the unexpected intercellular messenger and transmitter nitric oxide (NO) was the highlight of highly competitive investigations to identify the nature of endothelium-derived relaxing factor. This labile, gaseous molecule plays obligatory roles as one of the most promising physiological regulators in cardiovascular function. Its biological effects include vasodilatation, increased regional blood perfusion, lowering of systemic blood pressure, and antithrombosis and anti-atherosclerosis effects, which counteract the vascular actions of endogenous angiotensin (ANG) II. Interactions of these vasodilator and vasoconstrictor substances in the circulation have been a topic that has drawn the special interest of both cardiovascular researchers and clinicians. Therapeutic agents that inhibit the synthesis and action of ANG II are widely accepted to be essential in treating circulatory and metabolic dysfunctions, including hypertension and diabetes mellitus, and increased availability of NO is one of the most important pharmacological mechanisms underlying their beneficial actions. ANG II provokes vascular actions through various receptor subtypes (AT1, AT2, and AT4), which are differently involved in NO synthesis and actions. ANG II and its derivatives, ANG III, ANG IV, and ANG-(1-7), alter vascular contractility with different mechanisms of action in relation to NO. This review article summarizes information concerning advances in research on interactions between NO and ANG in reference to ANG receptor subtypes, radical oxygen species, particularly superoxide anions, ANG-converting enzyme inhibitors, and ANG receptor blockers in patients with cardiovascular disease, healthy individuals, and experimental animals. Interactions of ANG and endothelium-derived relaxing factor other than NO, such as prostaglandin I2 and endothelium-derived hyperpolarizing factor, are also described.
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PMID:Interaction of endothelial nitric oxide and angiotensin in the circulation. 1732 48

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.
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PMID:Vascular benefits of angiotensin receptor blockers. 1759 84


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