Central role of the AT1-receptor in atherosclerosis

Nickenig, Georg

doi:10.1038/sj.jhh.1001436

Cited by 68 publications

(56 citation statements)

References 88 publications

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“…AT 1 receptor antagonists block the oxidative stress induced in these cells by Ang II. 54,55 The redox-sensitive nuclear transcription factor NF-B appears to be an important link between AT 1 receptor activation, oxidative stress, and the inflammatory phenotype that is assumed by Ang II-responsive cells. 56 Activation of NF-B by the AT 1 receptor induces redox-sensitive genes for certain endothelial CAMs (eg, VCAM-1), cytokines (eg, tumor necrosis factor [TNF]-␣), and chemokines (monocyte chemoattractant protein-1).…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

“…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. 54,55 The possibility that Ang II and AT 1 receptors are involved in eliciting the oxidative stress and leukocyte-endothelial cell adhesion of hypercholesterolemia is supported by studies of both large and microscopic blood vessels.…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

“…45,54,55 This response is prevented by statin treatment through a mechanism that is independent of the drugs' lipid-lowering effect. 54,55 The possibility that Ang II and AT 1 receptors are involved in eliciting the oxidative stress and leukocyte-endothelial cell adhesion of hypercholesterolemia is supported by studies of both large and microscopic blood vessels. 52,65 Furthermore, surrogate markers for endothelial activation and inflammation (eg, sVCAM-1) indicate that RAS-directed drugs might exert some of their beneficial effects by controlling the inflammatory response that accompanies CVD.…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

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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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Section: Renin-angiotensin Systemmentioning

confidence: 99%

Section: Renin-angiotensin Systemmentioning

confidence: 99%

Section: Renin-angiotensin Systemmentioning

confidence: 99%

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Modulation of the Inflammatory Response in Cardiovascular Disease

2004

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“…Angiotensin II (AngII) through the angiotensin type 1 receptor (AT1 or AGTR1 as listed in the MGI database) is a powerful vasoconstrictor and a key hormone controlling plasma volume and is thus highly interesting to the realm of hypertension research (Nickenig 2002, Wassmann & Nickenig 2006. However, AngII is proving itself more ubiquitous in its importance to homeostasis outside its well-characterized hypertensive effects.…”

Section: Introductionmentioning

confidence: 99%

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

Snyder

Thekkumkara²

2011

Journal of Molecular Endocrinology

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Transcriptional repression through cis-and trans-acting factors enabling an alternate approach to control angiotensin type 1 receptor (AT1 or AGTR1 as listed in the MGI database) expression has not been studied. In previous investigations, treatment with retinoic acid was found to be associated with enhanced insulin sensitivity. In our previous study, expression of AT1 was found to be inversely correlated with intracellular glucose concentrations. Therefore, we hypothesized that 13-cis-retinoic acid (13cRA), an antioxidant, enhances insulin-sensitive glucose-mediated downregulation of the AT1. In this study, we used continuously passaged rat liver epithelial cells. Our study shows that cells exposed to 13cRA specifically down-regulated the AT1 protein in a dose-and time-dependent manner, independently of any change in receptor affinity. Down-regulation of the AT1 expression leads to reduced AngII-mediated intracellular calcium release, a hallmark of receptor-mediated intracellular signaling. Similarly with receptor down-regulation, we observed a significant reduction in AT1 mRNA; however, the AT1 down-regulation was independent of insulin-sensitive glucose uptake and retinoic acid receptor activation (RAR/RXR). Treatment with 13cRA resulted in phosphorylation of p42/p44 MAP kinases in these cells. Subsequent studies using MEK inhibitor PD98059 prevented 13cRA-mediated AT1 down-regulation and restored AngII-mediated intracellular calcium response. Furthermore, 13cRA-mediated inhibitory effects on AT1 were validated in primary rat aortic smooth muscle cells. In summary, our results demonstrate for the first time that 13cRA has a glucose-and RAR/RXR-independent mechanism for transcriptional inhibition of AT1, suggesting its therapeutic potential in systems in which AT1 expression is deregulated in insulin-sensitive and -insensitive tissues.

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“…4 -6 Because of these multiple interactions of AT1 receptors with vascular and white blood cells, it is thought that AT1 receptor activation is closely linked to the onset and progression of endothelial dysfunction and atherosclerosis. 2,4,5,7 Treatment of animals prone to develop atherosclerosis with angiotensin II leads to enhanced atherosclerotic lesion formation. 5,8,9 Risk factors such as hypercholesterolemia induce vascular AT1 receptor overexpression, which leads to increased oxidative stress and atherosclerosis.…”

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confidence: 99%

Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice

et al. 2004

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Background— Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis. Methods and Results— Apolipoprotein E–deficient (ApoE −/− ) mice were crossed with AT1A receptor–deficient (AT1 −/− ) mice to obtain homozygous double-knockout animals (ApoE −/− -AT1 −/− mice). Wild-type (C57BL/6J), ApoE −/− , AT1 −/− , and ApoE −/− -AT1 −/− mice were fed a high-cholesterol diet for 7 weeks. In contrast to wild-type and AT1 −/− mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE −/− mice. In the age-matched ApoE −/− -AT1 −/− littermates, development of diet-induced endothelial dysfunction and atherosclerotic lesion formation was profoundly inhibited. Concomitantly, aortic release of superoxide radicals was increased 2-fold in ApoE −/− mice compared with wild-type animals, whereas aortic superoxide production was normalized in ApoE −/− -AT1 −/− mice (L-012 chemiluminescence). There were no significant differences in plasma cholesterol levels between ApoE −/− and ApoE −/− -AT1 −/− animals. Systolic blood pressure was significantly lower in ApoE −/− -AT1 −/− animals than in ApoE −/− mice (tail-cuff measurements). Oral treatment of ApoE −/− mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function. Conclusions— Genetic disruption of the AT1A receptor leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in ApoE −/− mice irrespective of blood pressure and plasma cholesterol levels. These results indicate a fundamental role of AT1 receptor activation in atherogenesis.

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Central role of the AT1-receptor in atherosclerosis

Cited by 68 publications

References 88 publications

Modulation of the Inflammatory Response in Cardiovascular Disease

Modulation of the Inflammatory Response in Cardiovascular Disease

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice

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