The potential role of AT1-receptor blockade in the prevention and reversal of atherosclerosis

Papademetriou, Vasilios

doi:10.1038/sj.jhh.1001437

Cited by 13 publications

(9 citation statements)

References 45 publications

(40 reference statements)

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“…2,3,40 Recent evidence also points to the possibility that Ang II (acting through AT1-R) may contribute to the inflammatory responses associated with hypercholesterolemia, a condition known to increase the density of AT1-R on endothelial cells and circulating blood cells. 19,33,34 In the present study, we assessed the potential role of AT1-R in mediating the platelet-endothelial and leukocyte-endothelial cell adhesion elicited in the microvasculature by hypercholesterolemia. Our results indicate that AT1-R engagement contributes to the prothrombogenic and proinflammatory phenotype induced in postcapillary venules by hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…30 -32 Furthermore, AT1-R antagonists blunt the atherogenic responses to elevated cholesterol levels and attenuate hypercholesterolemia-induced endothelial cell dysfunction. 3,33,34 Nonetheless, it remains unclear whether and how the AT1-R contributes to the early microvascular alterations elicited by hypercholesterolemia.…”

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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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“…Similar results were reported in Watanabe rabbits. 14 The mechanism underlying the decrease in atherosclerosis after AT 1 blockade is unknown. Various groups have reported that angiotensin receptor blockers modulate cellular adhesion molecules in atherosclerosis, 15 decrease macrophage accumulation 16 and chemokine expression, 16 and attenuate LDL oxidation.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model

et al. 2004

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Background-Little is known about whether direct angiotensin receptor blockade can reduce atherosclerosis and plaque disruption. This study evaluated the effect of angiotensin receptor blockade on both the development of atherosclerosis and the disruption of plaque in a modified Constantinides animal model. Methods and Results-Twenty-eight New Zealand White rabbits underwent aortic balloon injury followed by a 1% cholesterol diet for 8 weeks. Thirteen rabbits received candesartan at 0.5 mg · kg Ϫ1 · d Ϫ1 beginning 2 days before aortic balloon injury and continued for the total 8 weeks of the cholesterol diet. The rabbits were then pharmacologically triggered and humanely killed, and their aortas were analyzed. The degree of atherosclerosis was determined by intima-media ratio of the infrarenal portion of the aorta. The frequency of intra-aortic thrombosis, a measure of plaque disruption, and the percentages of macrophage area and collagen-staining area of the plaque were determined. Candesartan-treated rabbits had less atherosclerosis (intima-media infrarenal aorta ratio of 1.18Ϯ0.08 versus 1.57Ϯ0.08[meanϮSEM] for the placebo group, PϽ0.001); fewer thrombi (3 of 13 versus 11 of 15; PϽ0.05); lower percentage area of macrophages to total plaque (18.8Ϯ2.7% versus 27Ϯ2.5%, PϽ0.05); and higher collagen to total plaque area (45Ϯ3% versus 35Ϯ2%, PϽ0.01).Conclusions-These results demonstrate that angiotensin receptor blockade attenuates the degree of atherosclerosis and reduces both plaque disruption and macrophage accumulation while increasing collagen deposition in the aortas of this animal model.

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“…61 Although there is limited evidence for the involvement of inflammation-dependent processes in the protective effects of AT 1 receptor antagonists in myocardial infarction 62 and stroke, 63 a more compelling case can be made for the involvement of Ang II and AT 1 receptors in the inflammatory responses associated with hypercholesterolemia and atherosclerosis. 64 Hypercholesterolemia is associated with an increased density of AT 1 receptors on endothelial cells, circulating leukocytes, and platelets. 45,54,55 This response is prevented by statin treatment through a mechanism that is independent of the drugs' lipid-lowering effect.…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

Modulation of the Inflammatory Response in Cardiovascular Disease

2004

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Abstract-There is a growing body of evidence that inflammation might play an important role in the initiation and progression of cardiovascular diseases (CVDs). The designation of CVD as a chronic inflammatory process is further supported by evidence that the risk factors for CVD cause endothelial cells throughout the vascular tree to assume an inflammatory phenotype. These activated endothelial cells characteristically exhibit oxidative stress and increased adhesiveness for circulating leukocytes. Although initial efforts to define the mechanisms underlying the inflammatory phenotype in diseased endothelial cells have focused on the linkage between oxidative stress and adhesion molecule activation/expression, recent work has implicated a variety of additional factors that can modulate the magnitude and/or nature of the inflammatory responses in CVD. Platelets, angiotensin II, and the CD40/CD40 ligand signaling system are gaining recognition as contributors to the pathogenesis of CVD. These factors appear to converge with known pathways that link oxidative stress with adhesion molecule expression and help to explain the apparent integration of coagulation with inflammation in CVD. These factors also hold the promise of offering multiple sites for therapeutic intervention in CVD. Key Words: oxidative stress Ⅲ integrins Ⅲ angiotensin II Ⅲ adhesion molecules I nflammation is gaining widespread attention for its role in the initiation and progression of cardiovascular disease (CVD). Epidemiological studies have revealed strong associations between biochemical markers of systemic inflammation and both the presence of and future risk for symptomatic CVD. Animal experimentation as well as clinical studies has provided convincing evidence that the known risk factors for CVD (hypertension, diabetes, hypercholesterolemia, and smoking) can elicit both an inflammatory and a prothrombogenic phenotype in the vascular system. The phenotypic changes are more pronounced in endothelial cells and can include oxidative stress, increased expression of endothelial cell adhesion molecules (CAMs), activation of cell signaling pathways (eg, the CD40/CD40 ligand [CD40L] dyad), and the consequent adhesion and activation of leukocytes and platelets. In the microcirculation, the inflammatory manifestations of CVD are more readily visible in postcapillary venules. There is growing evidence, however, that the endothelium-dependent arteriolar dysfunction often associated with CVD is also linked to the systemic inflammatory response. [1][2][3][4] Because the expression of adhesion glycoproteins by activated endothelial cells is a rate-determining step in the recruitment of inflammatory cells, much attention has been devoted to the role of endothelial CAMs in CVD. This attention has produced considerable evidence for the: (1) altered endothelial CAM expression in animal models of CVD 2,5 ; (2) use of circulating levels of soluble endothelial CAMs (eg, soluble intercellular adhesion molecule-1 [sICAM-1]) as a marker for the severity of inflammati...

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The potential role of AT1-receptor blockade in the prevention and reversal of atherosclerosis

Cited by 13 publications

References 45 publications

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

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

Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model

Modulation of the Inflammatory Response in Cardiovascular Disease

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