Degradation of Human Adrenomedullin(1-52) by Plasma Membrane Enzymes and Identification of Metabolites

Lewis, Lynley K.; Smith, Mary W.; Brennan, Stephen O.; Yandle, Timothy G.; Richards, A. Mark; Nicholls, M. Gary

doi:10.1016/s0196-9781(97)00005-3

Cited by 58 publications

(54 citation statements)

References 17 publications

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“…19,20 Even if NEP were involved in ADM degradation in the study of Lisy et al, 15 their findings could reflect a species difference or, more likely, a tissue difference. The kidney is particularly rich in NEP, and this may explain the discrepancy between the present findings and those of Lisy et al 15 However, the only other study we can find in the literature on the possible role of NEP in the metabolism of ADM suggests that even in the kidney, NEP may not metabolize ADM. 21 Lewis et al 21 CABG indicates coronary artery bypass graft surgery; NYHA, New York Heart Association; MI, myocardial infarction; CHD, coronary heart disease; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A.…”

Section: Discussionmentioning

confidence: 99%

Effect of Neutral Endopeptidase Inhibition on the Actions of Adrenomedullin and Endothelin-1 in Resistance Arteries From Patients With Chronic Heart Failure

Petrie

Hillier²,

Johnston³

et al. 2001

Hypertension

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Abstract-Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (nϭ8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (nϭ8). The values of corresponding Ϫlog concentrations of agonist required to effect a 50% response (pD 2 ) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.

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Section: Discussionmentioning

confidence: 99%

Effect of Neutral Endopeptidase Inhibition on the Actions of Adrenomedullin and Endothelin-1 in Resistance Arteries From Patients With Chronic Heart Failure

Petrie

Hillier²,

Johnston³

et al. 2001

Hypertension

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“…In line with this hypothesis, degradation of adrenomedullin to smaller fragments by plasma membrane enzymes and matrix metalloproteinase-2 was shown. 174,175 However, the antimicrobial activity of the fragments remains to be determined. In a study aiming to investigate the role of adrenomedullin in oral health, comparable concentrations were determined in serum and saliva (4.2 ng/ml and 4.9 ng/ml respectively).…”

Section: Truly Multifunctional Peptides and Proteinsmentioning

confidence: 99%

Antimicrobial peptides: The ancient arm of the human immune system

Wiesner¹,

Vilcinskas²

2010

Virulence

611

559

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The production of peptides and small proteins with microbicidal activity collectively called antimicrobial peptides (AMPs) is commonly considered to be a primitive mechanism of immunity and has been extensively studied in insects and other non-vertebrate organisms. In addition, a variety of AMPs present in amphibian skin secretion has been well characterised. There is now increasing evidence that AMPs play a crucial role in human immunity as well. Virtually all human tissues and cells typically exposed to microbes are able to produce AMPs. Important AMPs belonging to two structurally distinct classes, known as the defensins and the cathelicidins, are mainly produced by epithelial cells and neutrophils. AMPs significantly contributing to the chemical skin barrier are represented by dermcidin, psoriasin and RNase 7. The antimicrobial activity of saliva largely depends on histidine-rich AMPs known as histatins. Many more, in part less well-known AMPs and AMP-like proteins exist that exhibit various additional functions, apart from their antimicrobial properties. Among them, the neutrophil granule proteins azurocidin and cathepsin G are members of a family of serine-protease homologues called serprocidins and play a role in the regulation of the immune response and degradation of extracellular matrix proteins respectively. As another AMP-like protein of the neutrophil granule content, bactericidal/permeability increasing protein (BPI) is both able to permeabilise bacterial membranes and to function as an opsonin. The whey acidic protein (WAP) domain containing class of AMPs, including secretory leukocyte protease inhibitor (SLPI), elafin and trappin-2, is equally important in inhibition of neutrophil serine proteases and killing of microbes. Certain CC or CXC chemokines are known to possess antimicrobial properties and therefore are called kinocidins. Several kinocidins, including thrombocidin-1 and -2, are contained in the ?-granules of platelets. A cytoplasmic AMP described as ubiquicidin turned out to be identical with the strongly basic ribosomal protein S30. Proteolytic cleavage of the histone protein H2A in the stomach gives rise to an AMP initially described as buforin I. Adrenomedullin is a hormone-like AMP exhibiting vasodilatory and hypotensive effects. Lysozyme is mainly known for its cell wall degrading activity, but is also capable of non-enzymatic killing of bacteria. An iron-binding protein present in milk and other secretions named lactoferrin was shown to possess antimicrobial and antiviral activity and has been implicated in protection against cancer. Clinical studies on the treatment of infectious diseases have been performed with artificial peptides derived from human lactoferrin, histatins and BPI in addition to porcine protegrins, frog magains and bovine indolicidin. Omiganan, representing an indolicidin derivative, has been demonstrated to be effective in the treatment of acne and catheter-related local infections and is currently considered to be the most promising AMP-based drug candidate

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“…This degradation can be prevented in vitro by metalloprotease inhibitors. 99 From a therapeutic viewpoint, it may become possible to reduce the rate of degradation of the peptide, thus enhancing its biologic activity, or to augment its production. In theory, at least, such maneuvers could be therapeutically beneficial for patients with disorders such as heart failure or hypertension.…”

Section: Overviewmentioning

confidence: 99%