Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Vascular structure, function, and mechanics are altered in hypertension, which contributes to an important degree to complications of elevated blood pressure. Vascular hypertrophy with collagen deposition and increased stiffness is found in large arteries, whereas in small arteries, smooth muscle cells are restructured around a smaller lumen, and there is no net growth of the vascular wall, particularly in milder forms of hypertension. Hypertrophic remodeling and increased small artery stiffness may be found in more severe hypertension. Endothelial dysfunction occurs in large or smaller vessels in a variable percentage of patients, particularly in presence of other risk factors such as diabetes, smoking, dyslipidemia, and advanced atherosclerosis. In clinical trials, 1-year treatment with angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long-acting calcium channel blockers corrected small artery structure and endothelial dysfunction in hypertensive patients, whereas beta-adrenergic receptor blockers did not. Improved outcomes in hypertensive patients demonstrated in recent trials with some but not others of these agents could be a consequence, at least in part, of vascular protection offered by some antihypertensive agents.
...
PMID:Small artery remodeling in hypertension: can it be corrected? 1146 50

Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.
...
PMID:Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. 1148 44

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.
...
PMID:Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. 1160 27

Upregulation of angiotensin II receptor, may be involved in the initiation and progression of atherosclerosis. To examine the contribution of AT1 receptor in the expression of matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor (TIMP-2) in lipid-deposited arterial tissues, New Zealand white rabbits were given high-cholesterol chow (with losartan 25 mg/d or vehicle) for 10 weeks. Losartan reduced the areas of sudanophilia in the aorta of rabbits fed high-cholesterol diet (p < 0.01 vs. control). Losartan also significantly decreased the enhanced mRNA expression of MMP-1 and TIMP-2 in aortas of rabbits with high-cholesterol diet. Losartan-treated rabbits revealed a reduction in immunohistochemical expression of MMP-1, whereas TIMP-2 expression became localized to the intima. In addition, losartan treatment reduced the activation of NF-kappa B by inhibiting the degradation of its inhibitor I kappa-B alpha. These observations demonstrate that AT1 receptor blockade with losartan reduces lipid deposition and exerts potent inhibitory effects on NF-kappa B activation and modulates the expression of MMP-1 and TIMP-2 in hypercholesterolemic rabbits.
...
PMID:Modulation of matrix metalloproteinase-1, its tissue inhibitor, and nuclear factor-kappa B by losartan in hypercholesterolemic rabbits. 1186 11

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.
...
PMID:Recent advances in angiotensin II signaling. 1221 72

Atherosclerosis is associated with increased angiotensin II AT1-receptor expression and vascular hyperresponsiveness to angiotensin II. Nevertheless, atherosclerosis is often not accompanied by hypertension. We studied if the hypertensive effect of angiotensin II is more pronounced in atherosclerosis. Rabbits were fed a high-cholesterol diet (n = 10) for 12 weeks, followed by a standard diet for another 6 weeks. Control animals received the standard diet (n = 8) for 18 weeks. After 18 weeks, haemodynamic measurements were performed during a baseline recording and during an intravenous infusion of angiotensin II (0.4 microg kg-1 min-1). Atherosclerosis in the high-cholesterol group was verified by histological and lipidchemical tissue examinations. During angiotensin II infusion, total peripheral resistance (TPR) increased more in the high-cholesterol group than in controls (+81.6 +/- 12.4 vs. +40.6 +/- 9.7 mmHg min L-1, P < 0.05). While cardiac output and stroke volume (SV) decreased more in the high-cholesterol group (P < 0.05), reflex bradycardia was stronger in the control group (P < 0.05), indicating a reduced baroreceptor reflex sensitivity in atherosclerosis. Despite the larger increase in TPR and the reduced baroreceptor reflex sensitivity in the high-cholesterol group, maximum blood pressure response to angiotensin II was similar in both groups. The lack of a greater blood pressure response to angiotensin II in the high-cholesterol group could be the result of the early stages of heart failure. Under resting conditions, heart failure seems to be fully compensated, as baseline haemodynamic parameters were similar in the high-cholesterol group and in controls. However, during angiotensin II infusion, the compensatory mechanisms do not prevent a stronger fall in cardiac output and SV. Therefore, the blood pressure response to angiotensin II is not exaggerated in atherosclerotic animals, as vascular hyperresponsiveness to angiotensin II is opposed by the stronger fall in cardiac output and SV.
...
PMID:Cardiovascular responses to angiotensin II in atherosclerosis. 1235 68

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
...
PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

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.
...
PMID:[Angiotensin II receptor and oxidative stress]. 1239 80

We investigated in mice whether atherosclerosis exacerbates the development of post-ischemic heart failure and alters the beneficial effects of long-term angiotensin II type 1 receptor blockade in this model. ApoE-deficient (ApoE(-/-)) and C57BL/6J (C57) mice with myocardial infarction (coronary ligation) received vehicle (C57 and ApoE(-/-)) or irbesartan (Ir, 50mg/kg/d orally, C57-Ir and ApoE(-/-)-Ir). Ten months post myocardial infarction, survival rates were similar in C57 (58%) and ApoE(62%). Atherosclerosis induced no significant alteration in blood pressure, cardiac output (fluospheres), total peripheral resistance, or shortening fraction (echocardiography) but increased renal resistance (+50%, P<0.05). Chronic Ir treatment significantly improved survival to a similar extent in both C57-Ir (85%) and ApoE(-/-)-Ir (86%). It also decreased blood pressure to a similar extent in both strains (-16% and -18%, both P<0.05). In C57-Ir mice, Ir did not modify cardiac output or total peripheral resistance, but it decreased renal resistance (-28%, P<0.001) and left-ventricular weight (-28%, P<0.05). In ApoE(-/-)-Ir mice, Ir limited atherosclerotic lesions (-13%, P<0.05), increased cardiac output (+28%, P<0.05) and shortening fraction (+24%, P<0.05), and decreased total peripheral resistance (-33%, P<0.01), renal resistance (-61%, P<0.001), and left-ventricular weight (-27%, P<0.001). In conclusion, atherosclerosis does not worsen heart failure development in mice and, although the beneficial cardiovascular effects of AT1 receptor blockade are greater in ApoE(-/-) than in C57, reduction in mortality is similar in both strains.
...
PMID:Effects of angiotensin II type 1 receptor blockade in ApoE-deficient mice with post-ischemic heart failure. 1282 21

EFFICACY OF CALCIUM ANTAGONISTS: Calcium-channel blockers (CCBs) have long been recognized as potent agents for hypertensive therapy, with substantial blood pressure reduction in all age groups and races. CCBs improve endothelial function, may positively influence atherosclerosis in carotid arteries, reduce left ventricular hypertrophy, and hypertrophy of the resistance vessels, and improve arterial compliance. They do not adversely affect lipids and serum glucose. USE IN PRACTICE: CCBs are also a heterogenous class of drugs composed of the phenylalkylamine verapamil, the benzothiazepine diltiazem, and the large group of dihydropyridines (DHPs) with the prototype nifedipine, and an increasing number of newer agents (e. g. nitrendipine, nisoldipine, amlodipine, felodipine, lacidipine and lercanidipine). DHPs are primarily vasodilators, lowering blood pressure by decreasing peripheral vascular resistance at the level of the small arterioles which can be followed by an autonomic counterregulation especially in drugs with a rapid onset of action. This is markedly reduced or abolished in the treatment with the modern long acting DHPs and is also not the case in the treatment with non-DHPs. Prospective randomized controlled outcome studies demonstrated a significant reduction in stroke in elderly patients with isolated systolic hypertension compared with placebo (Syst-Eur [Syst-China]), and no significant differences in cardiovascular mortality and combined morbidity compared with diuretics, beta blockers or ACE-Inhibitors (STOP-2, INSIGHT, NORDIL, ALLHAT, INVEST). To normalize the blood pressure it is mostly necessary to combine antihypertensive drugs. Here are CCBs ideal partners for a therapy with ACE-inhibitors, AT1 antagonists or beta blockers (DHP) and diuretics (verapamil). With respect to the antihypertensive differential therapy the author recommends CCBs based on studies with the evidence grade 1-3; especially for elderly hypertensives (with isolated systolic neuhypertension and a high risk of stroke), for patients with COPD and asthma bronchiale, Raynaud's syndrome or Prinzmetal-angina, patients with diastolic function disturbances including diastolic heart failure or hypertensives with massive left ventricular hypertrophy (in combination with ACE or AT1 inhibitors).
...
PMID:[Differential therapy with calcium antagonists]. 1468 11


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

---