Identification of a human neutrophil angiotension II-generating protease as cathepsin G.

Tonnesen, Marcia G.; Klempner, Mark S.; Austen, K. Frank; Wintroub, Bruce U.

doi:10.1172/jci110437

Cited by 99 publications

(48 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been suggested that cathepsin G may play a role in the development of hypertension, based on its ability to convert both angiotensinogen [15] and angiotensin I [16] directly to angiotensin 11. Human cathepsin G has also been reported to cleave myosin and thus may be involved in muscle catabolism [17].…”

mentioning

confidence: 99%

Similarities between human and rat leukocyte elastase and cathepsin G

Virca

Metz

Schneble

1984

European Journal of Biochemistry

View full text Add to dashboard Cite

Rat is a likely test animal for determining the efficacy of proteinase inhibitor drugs directed toward human leukocyte elastase and cathepsin G. We therefore sought to assess and compare relevant properties of both human and rat leukocyte elastase and cathepsin G. Some differences between the pairs of proteinases from the two species were found, however both pairs of enzymes displayed comparable specificity toward various natural (plant and animal) proteinase inhibitors and also toward specific peptide substrates and a serine proteinase-specific reagent. Such overlapping specificity implies similarity of reactive center topography and sequence homology around the extended substrate/inhibitor binding regions of these proteinases. This apparent homology leads us to conclude that a pharmacologically effective inhibitor of leukocyte proteinases in the rat would probably also be effective in man.Human leukocyte elastase is arguably the most destructive enzyme present in the body. Its ability to degrade virtually all connective tissue components [l -31 has implicated its involvement in a wide variety of pathological conditions [I, 4 -141. Although the body normally possesses abundant levels of endogenous proteinase inhibitors, two of which (a-1 -proteinase inhibitor and a-2-macroglobulin) react very rapidly with human leukocyte elastase, elastase-mediated destruction of tissue nevertheless may occur when the enzyme/inhibitor balance is upset in favor of elastase. This suggests a potential therapeutic value for human leukocyte elastase-specific proteinase inhibitor drugs.Human cathepsin G has been implicated in a wide, and seemingly unrelated variety of disease processes by virtue of its ability to cleave many physiologically important proteins. It has been suggested that cathepsin G may play a role in the development of hypertension, based on its ability to convert both angiotensinogen [15] and angiotensin I [16] directly to angiotensin 11. Human cathepsin G has also been reported to cleave myosin and thus may be involved in muscle catabolism [17]. Fibronectin is cleaved into a reproducible set of fragments by the enzyme [IS] thus implicating cathepsin G in the regulation of fibronectin-mediated processes, such as cell adhesion [19], cell motility [20] and cell migration [21]. Although the involvement of cathepsin G in disease is less well documented than, e. g. human leukocyte elastase in emphysema [S -101, if the enzyme is inappropriately regulated Abhreviutions. %,PI, human alpha-I -proteinase inhibitor; Ac-AlaAla-(aza)Nle-ONp), acetyl-L-alanine-L-alanine-u-azanor-leucine-pnitrophenyl ester; Ac-Phe-ONp, N-acetyl-L-phenylalanine-p-nitrophenyl ester; Bz-Tyr-pNA, benzoyl-L-tyrosine-p-nitroanilide; BzTyr-OEt, N-benzoyl-L-tyrosine ethyl ester; HSA, human serum albumin; MeO-Suc-Ala-Ala-Pro-Phe-pNA, methoxy succinyl-L-ala-Enzymes. Leukocyte cathepsinG, both rat and human (EC 3.4.21.20); leukocyte elastase, both rat and human (EC 3.4.21.11). extracellularly the organism will likely suffer deleterious effects.Since anim...

show abstract

mentioning

confidence: 99%

Similarities between human and rat leukocyte elastase and cathepsin G

Virca

Metz

Schneble

1984

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…In 1974, Boucher, Asselin, and Genest 37 reported the first biochemical description of an alternative pathway to that of ACE for Ang II formation via tonin in the rat salivary gland. From 1976 to 1982, other reports of alternate Ang II forming enzymes included trypsin, 38 kallikrein, 39 and cathepsin-G. 40 Tonin, tissue plasminogen activator, and elastase were reported to generate Ang II either from angiotensinogen or Ang I. 41 Physiological evidence for the presence of alternative Ang II-forming mechanisms to ACE was first reported by Cornish, Joyner, and Gilmore in 1976.…”

Section: Non-standard Abbreviations and Acronymsmentioning

confidence: 99%

Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

Dell’Italia

2011

Circulation Research

View full text Add to dashboard Cite

show abstract

“…On the other hand, infiltration of inflammatory cells also could contribute to the local generation of angiotensin II during AP. It has been reported that neutrophil expresses cathepsin G on their membrane, which could actively convert angiotensinogen to angiotensin II (Tonnesen et al, 1982). Neutrophil could also promote angiotensin II generation via activation of prorenin (Dzau et al, 1987).…”

Section: Redox-sensitive Erk-induced Pancreatic Inflammation 453mentioning

confidence: 99%

Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells

Chan

Leung²

2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Angiotensin II has been shown to play a role in the pathogenesis of acute pancreatitis (AP). The present investigation aimed at elucidating redox-sensitive mechanistic pathway involved in proinflammatory actions of angiotensin II during an episode of AP; in particular, the regulation of expression of cytokine interleukin (IL)-6. Exogenous angiotensin II induced IL-6 expression, activation of extracellular-regulated kinase (ERK) 1/2, and superoxide generation in pancreatic acinar cell line AR42J, which were reversed by the angiotensin II type 1 (AT 1 ) receptor antagonist, losartan (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-methanol monopotassium salt, C 22 H 23 ClN 6 O). Pharmacological blockade of ERK1/2 improved angiotensin II-induced IL-6 expression. Moreover, angiotensin II-induced ERK1/2 activation was suppressed by antioxidant, indicating that redox-regulated ERK1/2 mediates the cytokine expression. cAMP-responsive element-binding protein (CREB) might be involved in ERK1/2-induced IL-6 expression because phosphorylation of CREB was observed after angiotensin II treatment, which was reversed by losartan and the ERK1/2 inhibitor. These results were in close agreement with the in vivo findings using an obstructive model of AP. Obstruction of the common biliopancreatic duct time-dependently enhanced angiotensinogen levels, which correlated well with superoxide generation, ERK1/2 and CREB phosphorylation, and subsequent IL-6 expression. It is more important that changes in these parameters were antagonized by prophylactic administration of losartan. These in vitro and in vivo results indicate that angiotensin II induces redox-regulated ERK1/2 and CREB activation, thus leading to IL-6 expression in an AT 1 receptormediated manner in pancreatic acinar cells during the pathogenesis of AP.

show abstract

Identification of a human neutrophil angiotension II-generating protease as cathepsin G.

Cited by 99 publications

References 33 publications

Similarities between human and rat leukocyte elastase and cathepsin G

Similarities between human and rat leukocyte elastase and cathepsin G

Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells

Contact Info

Product

Resources

About