Modulating atherosclerosis through inhibition or blockade of angiotensin

Rosenson, Robert S.

doi:10.1002/clc.4950260703

Cited by 19 publications

(11 citation statements)

References 53 publications

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“…Recipient (CD45 congenic WT) mice were irradiated with 2 doses of 500 to 525 Rads, 3 hours apart, after which 8ϫ10 6 donor bone marrow cells in 200 L of PBS were injected into the femoral vein. The chimeras were kept in autoclaved cages, with 0.2% neomycin drinking water for 2 weeks, after which normal drinking water was used.…”

Section: Production Of Bone Marrow Chimerasmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9] The renin-angiotensin system has also been implicated as a mediator of the deleterious consequences of the known risk factors for cardiovascular disease. For example, AT1-receptor (AT1-R) activation appears to play a major role in the development of the impaired endotheliumdependent vasodilation that is associated with hypercholesterolemia.…”

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confidence: 99%

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Role of Blood Cell–Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia

Petnehazy

Stokes²,

Wood³

et al. 2006

ATVB

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Objective-Hypercholesterolemia elicits a proinflammatory and prothrombogenic phenotype in the microvasculature that is characterized by activation and adhesion of blood cells. The angiotensin II receptor-1 antagonist Losartan prevents the induction of these responses. The objective of this study was to determine the relative contributions of blood cell-associated versus endothelium-associated AT1a-R to these hypercholesterolemia-induced microvascular alterations. Methods and Results-Leukocyte adhesion and emigration and platelet adhesion were quantified by intravital microscopy in postcapillary venules. C57Bl/6 mice were placed on a normal (ND) or high-cholesterol (HCD) diet for 2 weeks. AT1a-R bone marrow chimeras that express AT1a-R on the vessel wall but not blood cells and AT1a-R knockouts were placed on HCD. Venular shear rate was comparable in all groups. Platelet and leukocyte adhesion and leukocyte emigration were significantly increased in HCD mice versus ND. Leukocyte recruitment was significantly reduced in the HCD-AT1a-R bone marrow chimera group, whereas platelet adhesion remained at HCD levels. However, in HCD-AT1a-R knockout mice, platelet and leukocyte adhesion were reduced to ND levels. Conclusions-These data indicate that the platelet-vessel wall adhesion elicited by hypercholesterolemia is mediated by AT1a-R engagement on the endothelial cell rather than the platelet, whereas leukocyte recruitment is mediated by blood cell-associated AT1a-R. Key Words: angtiotensin II type 1 receptor Ⅲ microcirculation Ⅲ hypercholesterolemia Ⅲ platelets Ⅲ leukocytes W hereas the renin-angiotensin system has long been recognized for its contribution to the pathogenesis of hypertension, recent evidence implicates this regulatory pathway in a variety of other cardiovascular diseases, including atherosclerosis, diabetic vasculopathy, stroke, and myocardial infarction. 1-9 The renin-angiotensin system has also been implicated as a mediator of the deleterious consequences of the known risk factors for cardiovascular disease. For example, AT1-receptor (AT1-R) activation appears to play a major role in the development of the impaired endotheliumdependent vasodilation that is associated with hypercholesterolemia. 10 Angiotensin II can invoke microvascular alterations, including oxidative stress and the adhesion of leukocytes and platelets in postcapillary venules, by acting through AT1-R. 11,12 We have reported recently that the AT1-R antagonist Losartan attenuates the proinflammatory and prothrombogenic effects of hypercholesterolemia in the microvasculature, suggesting that AT1-R engagement on circulating blood cells and/or vascular endothelium is required for these responses. 13 Although the Losartan treatment studies provide circumstantial evidence that indicates a differential responsiveness of platelets, leukocytes, and endothelial cells to AT1-R activation, the experimental strategy used to date cannot definitively resolve the relative contributions of AT1-R on the different cell types to the overall blood cell ...

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Section: Production Of Bone Marrow Chimerasmentioning

confidence: 99%

mentioning

confidence: 99%

Role of Blood Cell–Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia

Petnehazy

Stokes²,

Wood³

et al. 2006

ATVB

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“…An important vascular effect of ANG II is its induction of oxidative stress and a proinflammatory phenotype. Type I ANG II (AT 1 ) receptor blockade can prevent the unfavorable vascular effects by ANG II through hypertension-dependent and -independent mechanisms (1,18,22). Our previous studies have demonstrated that, in addition to vascular remodeling, elevation of circulating ANG II levels also leads to extensive microscopic myocardial repair/remodeling in both left and right ventricles in rats (21, 22).…”

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confidence: 99%

ANG II-induced cardiac molecular and cellular events: role of aldosterone

Zhao

Ahokas²,

Weber³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic elevation of circulating ANG II is associated with cardiac remodeling in patients with hypertension and heart failure. The underlying mechanisms, however, are not completely defined. Herein, we studied ANG II-induced molecular and cellular events in the rat heart as well as their links to the redox state. We also addressed the potential contribution of aldosterone (ALDO) on ANG II-induced cardiac remodeling. In ANG II-treated rats, and compared with controls, we found: 1) the expression of proinflammatory/profibrogenic mediators was significantly increased in the perivascular space and at the sites of microscopic injury in both ventricles; 2) macrophages and myofibroblasts were primary repairing cells at these sites, together with increased fibrillar collagen volume; 3) apoptotic macrophages and myofibroblasts were evident at the same sites; 4) NADPH oxidase (gp91 phox ) was significantly enhanced at these regions and primarily expressed by macrophages, whereas superoxide dismutase and catalase levels remained unchanged; 5) plasma 8-isoprostane levels were significantly increased; and 6) blood pressure was significantly elevated. Losartan treatment completely prevented cardiac oxidative stress as well as molecular/cellular responses and normalized blood pressure. Spironolactone treatment partially suppressed the cardiac inflammatory/fibrogenic responses and redox state. Thus chronic elevation of circulating ANG II is accompanied by a proinflammatory/profibrogenic phenotype involving vascular and myocardial remodeling in both ventricles. Enhanced reactive oxygen species production at these sites and increased plasma 8-isoprostane indicate the involvement of oxidative stress in ANG II-induced cardiac injury. ALDO contributes, in part, to ANG II-induced cardiac molecular and cellular responses. cardiac remodeling; angiotensin II; aldosterone; oxidative stress; rats AS A CIRCULATING HORMONE, endocrine properties of ANG II are integral to the regulation of blood pressure and volume homeostasis. However, chronic elevation of circulating ANG II, such as occurs with congestive heart failure and hypertension, is inappropriate and has adverse consequences. For example, such neurohormonal activation has been related to a diverse number of vascular diseases, including atherosclerotic coronary artery disease, cardiac perivascular fibrosis, and diabetes (6,8). An important vascular effect of ANG II is its induction of oxidative stress and a proinflammatory phenotype. Type I ANG II (AT 1 ) receptor blockade can prevent the unfavorable vascular effects by ANG II through hypertension-dependent and -independent mechanisms (1,18,22). Our previous studies have demonstrated that, in addition to vascular remodeling, elevation of circulating ANG II levels also leads to extensive microscopic myocardial repair/remodeling in both left and right ventricles in rats (21, 22). However, ANG II-induced myocardial molecular/cellular events and their relation to oxidative stress have not been fully explored.ANG II stimulates aldosterone ...

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“…It is becoming increasingly accepted that Ang II, through its interaction with the AT1-R, is linked to CVD by promoting inflammation. 19,20 For example, clinical trials with AT1-R blockers show some benefit in reducing ischemic events and mortality related to CVD beyond blood pressure lowering, [21][22][23][24][25] and AT1-R antagonists inhibit LDL lipid peroxidation and development of atherosclerotic lesions in animal models of hypercholesterolemia. 26 It is well established that hypercholesterolemia elicits systemic inflammatory responses, which are characterized by an oxidative stress, elevated cytokines, and activation of blood cells.…”

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confidence: 99%

Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules

et al. 2005

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Abstract-Hypercholesterolemia elicits an inflammatory response in the microvasculature that is accompanied by an increased expression of angiotensin II type-1 receptors (AT1-R) on platelets, leukocytes, and endothelial cells. AT1-R blockade attenuates inflammatory responses to angiotensin II (eg, adhesion molecule expression and reactive oxygen species production). We investigated whether AT1-R antagonism attenuates the platelet and leukocyte recruitment induced by acute hypercholesterolemia in postcapillary venules. Leukocyte and platelet adhesion and oxidative stress were quantified by intravital microscopy in cremaster muscle, and P-selectin and AT1-R expression was determined in mice placed on a normal diet (ND) or high-cholesterol diet (HCD) for 2 weeks. Platelet and leukocyte adhesion was significantly elevated by hypercholesterolemia. In HCD mice receiving losartan (HCD-Los) in drinking water, platelet and leukocyte recruitment was reduced to ND levels. Increased platelet adhesion was observed in HCD mice receiving platelets from HCD-Los mice, consistent with a direct beneficial action of losartan on the vessel wall. Hypercholesterolemia elicited an oxidative stress in venules and an increased expression of P-selectin and AT1-R. The oxidative stress and AT1-R upregulation were reduced by losartan, but the P-selectin response was not. We propose that AT1-R engagement contributes to the prothrombogenic and proinflammatory state induced in venules by hypercholesterolemia. Key Words: receptors, angiotensin II Ⅲ microcirculation Ⅲ hypercholesterolemia Ⅲ leukocytes I t is well established that angiotensin II (Ang II), the effector component of the renin-angiotensin system, is a potent vasoconstrictor that plays a key role in the maintenance of blood pressure and fluid homeostasis. However, it is becoming increasingly apparent that Ang II also possesses potent proinflammatory properties, such as enhancing reactive oxygen species (ROS) generation, 1 increasing the expression of cell adhesion molecules (CAMs) and stimulating the release of cytokines and chemoattractants such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. 2-4 Ang II stimulates superoxide release from NAD(P)H oxidase by engaging the high-affinity Ang II type-1 receptor (AT1-R), thereby initiating the phosphorylation of critical enzyme subunits. 5,6 In vitro, Ang II elevates surface expression of CAMs 7 such as vascular CAM-1 (VCAM-1), 8 intercellular adhesion molecule-1 (ICAM-1), 9 and E-selectin. 10 In vivo, superfusion of postcapillary venules with Ang II results in leukocyte recruitment and ROS generation. 11,12 These leukocyte adhesion responses appear to be mediated by a ROSdependent mobilization of preformed P-selectin to the endothelial surface. 11,12 Ang II can act as an immunomodulatory agent that engages the AT1-R to increase the number of Th1 cytokine (interferon-␥)-producing T cells 13 and elevate CD40 expression on circulating monocytes. 14 Ang II may also exert some of its proinflammatory effects through activatio...

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Modulating atherosclerosis through inhibition or blockade of angiotensin

Cited by 19 publications

References 53 publications

Role of Blood Cell–Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia

Role of Blood Cell–Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia

ANG II-induced cardiac molecular and cellular events: role of aldosterone

Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules

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