Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression

Nickenig, Georg; Jung, Ok‐Sang; Strehlow, Kerstin; Zolk, Oliver; Linz, Wolfgang; Schölkens, Bernward A.; Böhm, Michael

doi:10.1152/ajpheart.1997.272.6.h2701

Cited by 117 publications

(123 citation statements)

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“…Although it remains unclear whether the subtle constitutive activity of the native AT 1 receptor has a pathophysiological role, the enhancement of its constitutive activity olmesartan Inverse agonist activity of olmesartan Y Qin et al through upregulation of receptor expression may promote cardiovascular remodeling. Indeed, the expression level of the AT 1 receptor in vascular cells is upregulated by low-density lipoprotein cholesterol, 13 insulin, 14 glucose, 15 progesterone 16 and inflammatory cytokines, such as interleukin-1a or interleukin-6. 17,18 Analyses of the binding affinity of olmesartan for mutant AT 1 receptors as well as molecular modeling analyses indicated that the ternary interactions between the hydroxyl group and Tyr 113 and between the carboxyl group and Lys 199 and His 256 are critical to the inverse agonist properties of olmesartan, but that the interaction between the tetrazole group and Gln 257 is dispensable.…”

Section: Discussionmentioning

confidence: 99%

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-

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Section: Discussionmentioning

confidence: 99%

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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“…13,14 Of interest, statins reverse the elevated blood pressure response to angiotensin II infusion and downregulate AT 1 receptor density. 15 Therefore, simvastatin combined with ramipril may reduce LDL cholesterol levels and angiotensin II expression, which would be predicted to improve flow-mediated dilation.…”

Section: Discussionmentioning

confidence: 99%

“…12 Recent studies have shown that LDL induces the expression of angiotensin II type-1 (AT 1 ) receptor upregulation and that hypercholesterolemic rabbits display enhanced vascular expression of AT 1 receptors. 13,14 Of interest, statins reverse the elevated blood pressure response to angiotensin II infusion and downregulate AT 1 receptor density. 15 Recent experimental studies have confirmed that angiotensin II accelerates the development of atherosclerosis.…”

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confidence: 99%

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

et al. 2004

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Abstract-Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30Ϯ5% and 53Ϯ6%, respectively (PϽ0.001), and reduced plasma levels of malondialdehyde by 4Ϯ7% (Pϭ0.026) and 25Ϯ4% (PϽ0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3Ϯ3% and 12Ϯ2%, respectively (Pϭ0.049 and Pϭ0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (Pϭ0.036 and PϽ0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by Ϫ7Ϯ7% and 17Ϯ5%, respectively (Pϭ0.828 and PϽ0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (PϽ0.001 and Pϭ0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (both PϽ0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (PϽ0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endotheliumdependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients. Key Words: angiotensin-converting enzyme Ⅲ atherosclerosis Ⅲ endothelial growth factors Ⅲ hypercholesterolemia Ⅲ blood pressure L arge-scale clinical studies demonstrate that statins and angiotensin-converting enzyme (ACE) inhibitor prevent or retard the progression of coronary heart disease. 1,2 The mechanisms of this apparent benefit of these therapies may include vascular effects. Statins reduce LDL cholesterol and improve endothelial function, consistent with enhanced NO bioactivity. 3-5 ACE inhibition also improves endothelial function. 6,7 A potential mechanism of this effect is augmented NO bioactivity via diminished bradykinin degradation by ACE with activation of endothelial B 2 kinin receptors and stimulation of NO synthase activity. 8 Alternatively, ACE inhibition may diminish intracellular production of superoxide anions via reduced activity of angiotensin II-dependent oxidases in the endothelium and vascular smooth muscle, 9,10 thus protecting NO from oxidant degradatio...

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“…In rabbits with diet-induced atherosclerosis or heritable hyperlipidaemia, aortic AT 1 -receptor expression is increased by two-fold. 89,90 This has functional significance, in that angiotensin IIinduced vasoconstriction is markedly increased in these animals. Interestingly, vascular superoxide production is also increased in hypercholesterolaemia, and this is associated with profound alteration of endothelium-dependent vasodilation.…”

Section: Regulation Of the At 1 -Receptormentioning

confidence: 98%

Central role of the AT1-receptor in atherosclerosis

Nickenig

2002

J Hum Hypertens

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The renin-angiotensin system plays a major role in the pathogenesis of atherosclerosis. Most known effects of angiotensin II are mediated via activation of the AT 1 -receptor, which is in turn influenced to a great degree by levels of expression of the AT 1 -receptor. AT 1 -receptor activation is not only involved in vasoconstriction, water and salt homoeostasis and control of other neurohumoral systems, but also induces reactive oxygen species production, cellular hypertrophy and hyperplasia and apoptosis. Expression of this G-proteincoupled receptor is regulated by multiple factors. Among other conditions, oestrogen deficiency and hypercholesterolaemia increase AT 1 -receptor expression. Experimental data suggest that this augments the actions of angiotensin II, contributes to endothelial dysfunction, increases vascular production of reactive oxygen species, and via these mechanisms Keywords: AT 1 -receptors; atherosclerosis; oxidised LDL; reactive oxygen species; renin-angiotensin system; vascular smooth muscle Angiotensin receptors and cellular functionThe principal effector of the renin angiotensin system, angiotensin II, modulates blood pressure, water and sodium homoeostasis, neuronal function, and other neurohumoral systems.1-3 Initial research with angiotensin II focused on its role in the pathogenesis of hypertension, but in the past decade increasing evidence has accumulated to indicate that this octapeptide is involved in the development of atherosclerosis, myocardial infarction, vascular and myocardial remodelling, and congestive heart failure. [4][5][6][7] The effects of angiotensin II are mediated by two receptors, referred to as the AT 1 -and AT 2 -subtypes. 3,4 In adult tissues, the AT 2 -receptor is predominantly expressed in the brain and adrenals, with lower levels expressed elsewhere.

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Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression

Cited by 117 publications

References 0 publications

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

Central role of the AT1-receptor in atherosclerosis

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