The endothelin system and its potential as a therapeutic target in cardiovascular disease

Journal of Biological Chemistry

Watson

Marlow

et al. 2003

242

176

The abnormal accumulation of ␤-amyloid (A␤) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of A␤. As with any peptide, however, the degree of A␤ accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an A␤-degrading enzyme that appears to act intracellularly, thus limiting the amount of A␤ available for secretion. To determine the physiological significance of this activity, we analyzed A␤ levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both A␤40 and A␤42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in A␤ levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting A␤ accumulation in the brain and also provides further insight into the factors involved in A␤ clearance in vivo.Alzheimer's disease (AD), 1 the most common cause of dementia in the elderly, is characterized pathologically by the accumulation of ␤-amyloid peptides (A␤40 and A␤42) in the brain. Although considerable attention has been focused on understanding the enzymes and processes involved in the production of A␤, very little is known regarding the processes by which A␤ is normally removed. This removal can be in the form of transport of the peptide into the cerebrospinal fluid for peripheral clearance, by binding to proteins that sequester the peptide in a nonreactive form, or by direct catabolism of A␤. A significant role for A␤ catabolism has been highlighted in a recent report by Saido and colleagues (1) in which they showed that infusion of the metalloprotease inhibitor thiorphan into the hippocampus of rats resulted in localized A␤ deposition, reportedly through the inhibition of A␤ degradation by neprilysin (NEP).A␤ catabolism appears complex. Recent reports suggest significant roles for insulin-degrading enzyme, NEP, and the plasmin system in the catabolism of A␤ (1-10). Angiotensin-converting enzyme, matrix metalloproteinase-9, EC 3.4.24.15, and ␣-2 macroglobulin complexes have also been reported to play a role in A␤ degradation on the basis of in vitro and cell-based assays (11)(12)(13)(14). To date, however, only neprilysin has been reported to influence A␤ levels in the brains of knock-out mice (1,5,15).Using pharmacological, molecular, and biochemical approaches, we have previously characterized endothelin-converting enzyme-1 (ECE-1) as a novel A␤-degrading enzyme that appears to act intracellularly to reduce the amount of A␤ available for secretion (16). Overexpression of ECE-1 in cells that lack endogenous ECE activity results in a pronounced decrease in A␤ accumulation in the...

Section: A␤ Levels Are Increased In Ece-deficient Mice 2082mentioning

confidence: 80%

Alzheimer's Disease β-Amyloid Peptide Is Increased in Mice Deficient in Endothelin-converting Enzyme

Journal of Biological Chemistry

Watson

Marlow

et al. 2003

242

176

“…First, ECE inhibitors have received a large amount of pharmaceutical interest for their potential as anti-hypertension drugs (60). If degradation of A␤ by ECE does, as we hypothesize, contribute to the extracellular concentration of the plaque-forming peptide in the brain, inhibiting this activity may lead to the development of AD and/or accelerate the disease in susceptible individuals.…”

Section: Discussionmentioning

confidence: 96%

Degradation of the Alzheimer's Amyloid β Peptide by Endothelin-converting Enzyme

Reed

Journal of Biological Chemistry

2001

319

245

Deposition of ␤-amyloid (A␤) peptides in the brain is an early and invariant feature of all forms of Alzheimer's disease. As with any secreted protein, the extracellular concentration of A␤ is determined not only by its production but also by its catabolism. A major focus of Alzheimer's research has been the elucidation of the mechanisms responsible for the generation of A␤. Much less, however, is known about the mechanisms responsible for A␤ removal in the brain. In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel A␤-degrading enzyme. We show that treatment of endogenous ECE-expressing cell lines with the metalloprotease inhibitor phosphoramidon causes a 2-3-fold elevation in extracellular A␤ concentration that appears to be due to inhibition of intracellular A␤ degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular A␤ concentration by up to 90% and that this effect is completely reversed by treatment of the cells with phosphoramidon. Finally, we show that recombinant soluble ECE-1 is capable of hydrolyzing synthetic A␤40 and A␤42 in vitro at multiple sites.

Clinical Cancer Research

“…The initial dose level was 5 mg/day, with subsequent planned dose levels of 10,20,30,45,60,75,95,115, and 140 mg/day. Three subjects were to be enrolled at each dose level.…”

Section: Methodsmentioning

confidence: 99%

“…ET A binds ET-1 with a higher affinity than the other ET isoforms, and this system has been implicated in tumor growth, angiogenesis, nociception, and bone deposition (5,9). ET B receptors mediate vasomotor tone and function as a clearance receptor (10).…”

Section: Introductionmentioning

confidence: 99%

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

Ryan

Vogelzang

Vokes

et al. 2004

Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET A . Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.