Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

Iwasa, Satoshi; Fan, Jianglin; Miyauchi, Takashi; Watanabe, Teruo

doi:10.1159/000048751

Cited by 17 publications

(18 citation statements)

References 38 publications

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“…The average intakes of the ET-1 antagonists were 30 mg/kg/day for the selective type A (ET A ) receptor antagonist FR139317 (Sogabe et al, 1993); 1 mg/kg/day for the selective ET-1 type B (ET B, ) (Ishikawa et al, 1994) receptor antagonist BQ-788; and 10 mg/kg/day for the nonselective ET A /ET B antagonist (Ohlstein et al, 1994) SB209670. These doses are in line with those used in other studies addressing the effect of chronic treatment (Fujihara et al, 1995;Kohzuki et al, 1998;Takeda et al, 1999;Iwasa et al, 2001). Antagonists were given over the entire period of treatment with prednisolone or with vehicle.…”

Section: Methodssupporting

confidence: 84%

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Filippo

Rossi²,

Ongini³

et al. 2004

J Pharmacol Exp Ther

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Daily administration of prednisolone, but not the derivative NCX-1015 (or prednisolone 21-[4Ј-nitrooxymethyl]benzoate), to rats resulted in a time-and dose-dependent increase in mean arterial blood pressure (MABP), significant after 1 week for the dose of 6.9 mol/kg i.p. (n ϭ 10; P Ͻ 0.05), and 3 weeks for the lower dose of 1.38 mol/kg. A similar dichotomy of behavior was observed with respect to myocardial contractility and renal vascular resistance, in either case augmented by 3-week treatment with prednisolone but not NCX-1015. In contrast, both NCX-1015 and prednisolone reduced plasma levels of corticosterone in a dose-(dose range of 0.69 -6.9 mol/kg i.p.) and time-dependent (1-3 weeks) manner. Similar profiles were obtained for plasma nitrate values, although they were increased selectively after NCX-1015 administration. In contrast, prednisolone, but not NCX-1015, augmented plasma endothelin 1 (ET-1) with a profile that mirrored the changes observed in MABP and renal blood flow. Supply in the drinking water of the ET-1 receptor typeantagonists prevented the changes produced by a 21-day treatment with prednisolone. In conclusion, this study indicates 1) a lack of occurrence of cardiovascular alterations by nitro-releasing derivative of prednisolone (NCX-1015), and 2) a functional link between prednisolone effects and the endogenous endothelin-1 system. Glucocorticoids (GCs) have wide clinical applications for the management of a variety of disorders, including autoimmune, allergic, and lymphoproliferative diseases. In most of these pathologies, GC must be administered for long term, and this increases the likelihood of the appearance of major side effects, thus limiting further use (Whitworth, 1994;Saruta, 1996). Marked side effects include obesity with the classical "moon face"; hirsutism; cataracts; osteoporosis; diabetes mellitus; immune suppression; and cardiovascular disorders, including hypertension and atherosclerosis (Ross and Linch, 1982;Schä cke et al., 2002). Among these multiple effects, cardiovascular complications are an important factor for predicting the morbidity and mortality of patients overtreated with GCs (Ross and Linch, 1982). Plasma volume expansion due to sodium retention gives a minor contribution to GC cardiovascular effects (Whitworth et al., 1989;Whitworth, 1994;Saruta, 1996). In contrast, increase in peripheral vascular resistance, demonstrated by an augmented pressor response to catecholamines and angiotensin II, is a major contributor to the pathogenesis of hypertension after excess use of GCs (Pirpiris et al., 1992;Whitworth, 1994;Saruta, 1996). The molecular mechanism whereby GC excess causes the increase in vascular resistance and hypertension has not been fully elucidated, although a recent study has provided a functional link between dexamethasone administration and down-regulation of endothelial nitric-oxide (NO) synthase (Wallerath et al., 2004

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Section: Methodssupporting

confidence: 84%

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Filippo

Rossi²,

Ongini³

et al. 2004

J Pharmacol Exp Ther

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“…As mentioned above, oxLDL can induce adhesion molecule expression on endothelial cells and trigger the migration of monocytes towards the intima. On the other hand, oxLDL can stimulate the production of many inflammatory mediators (e. g. endothelin-1) from other vascular cells, in turn resulting in diverse inflammatory responses in the arterial wall (36,37). Using apoE KO mice, our laboratory demonstrated that the chronic administration of endothelin-1 A/B receptor antagonist SB209670 results in a significant reduction of atherosclerosis, independent of the plasma levels of cholesterol (37).…”

Section: Lipoproteins and Inflammationmentioning

confidence: 95%

“…On the other hand, oxLDL can stimulate the production of many inflammatory mediators (e. g. endothelin-1) from other vascular cells, in turn resulting in diverse inflammatory responses in the arterial wall (36,37). Using apoE KO mice, our laboratory demonstrated that the chronic administration of endothelin-1 A/B receptor antagonist SB209670 results in a significant reduction of atherosclerosis, independent of the plasma levels of cholesterol (37). Therefore, it is likely that, similar to lipid-lowering drugs (such as statins), The lesion is stained with antibodies HAM for monocytes, HF35 for smooth muscle α -actin and apo (a), The lesion contains a thin cap beneath which a number of macrophages (B and C) are present.…”

Section: Lipoproteins and Inflammationmentioning

confidence: 99%

Inflammatory Reactions in the Pathogenesis of Atherosclerosis

Fan

Watanabe

2003

JAT

Self Cite

296

184

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Atherosclerosis and its complications constitute the most common causes of death in Western societies and Japan. Although several theories or hypotheses about atherogenesis have been proposed during the past decades, none can completely explain the whole process of the pathogenesis of atherosclerosis because this disease is associated with multiple risk factors. In spite of this, the concept that atherosclerosis is a specific form of chronic inflammatory process resulting from interactions between plasma lipoproteins, cellular components ( monocyte/macrophages, T lymphocytes, endothelial cells and smooth muscle cells ) and the extracellular matrix of the arterial wall, is now well accepted. Histologically, atherosclerotic lesions from the early-stage ( fatty streak ) to more complicated lesions possess all the features of chronic inflammation. It has been demonstrated that atherogenic lipoproteins such as oxidized low density lipoprotein ( LDL ), remnant lipoprotein (β -VLDL) and lipoprotein [ Lp ] ( a ) play a critical role in the pro-inflammatory reaction, whereas high density lipoprotein ( HDL ), anti-atherogenic lipoproteins, exert anti-inflammatory functions. In cholesterol-fed animals, the earliest events in the arterial wall during atherogenesis are the adhesion of monocytes and lymphocytes to endothelial cells followed by the migration of these cells into the intima. It has been shown that these early events in atherosclerosis are triggered by the presence of high levels of atherogenic lipoproteins in the plasma and are mediated by inflammatory factors such as adhesion molecules and cytokines in the arterial wall. The development of genetically modified laboratory animals ( transgenic and knock-out mice and transgenic rabbits ) has provided a powerful approach for dissecting individual candidate genes and studying their cause-and-effect relationships in lesion formation and progression. The purpose of this article is to review the recent progress regarding the inflammatory processes during the development of atherosclerosis based on both human and experimental studies. In particular, we will address the mechanisms of atherogenic lipoproteins in terms of inflammatory reactions associated with hypercholesterolemia. Understanding the molecular mechanisms responsible for inflammatory reactions during atherogenesis may help us to develop novel therapeutic strategies to control, treat and prevent atherosclerosis in the future. J Atheroscler Thromb, 2003; 10: 63-71.

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“…Recent genome‐wide association studies have implicated the ET A receptor as a genetic determinant of coronary artery disease,54, 55 carotid atherosclerosis,54 large‐artery stroke,55 and peripheral artery disease,56 suggesting a role of this receptor in atherogenesis across diverse arterial systems. These findings are supported by clinical and preclinical studies that suggest a direct role of the ET A receptor on the development of atherosclerosis 57, 58, 59, 60, 61. Recently, Gupta and colleagues demonstrated in a separate genome‐wide association study project that a single‐nucleotide polymorphism common in 5 vascular diseases, including coronary artery disease, promotes exaggerated endothelium‐derived ET‐1 and higher plasma ET‐1 62.…”

Section: Discussionmentioning

confidence: 83%

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Fox

Becker

Loria

et al. 2018

JAHA

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

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Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

Cited by 17 publications

References 38 publications

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Inflammatory Reactions in the Pathogenesis of Atherosclerosis

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

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