Hydrolysis of Angiotensin Peptides by Human Angiotensin I–Converting Enzyme and the Resensitization of B2 Kinin Receptors
Identifieur interne : 000774 ( Pmc/Corpus ); précédent : 000773; suivant : 000775Hydrolysis of Angiotensin Peptides by Human Angiotensin I–Converting Enzyme and the Resensitization of B2 Kinin Receptors
Auteurs : Zhenlong ChenSource :
- Hypertension [ 0194-911X ] ; 2005.
Abstract
We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I– converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B2 receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B2 receptors coupled to green fluorescent protein (B2GFP) or to express only coupled B2GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B2 receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18× slower than Ang I and ≈30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although μmol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B2GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B2 receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-α, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B2 activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B2 receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.
Url:
DOI: 10.1161/01.HYP.0000188905.20884.63
PubMed: 16246972
PubMed Central: 1564276
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PMC:1564276Le document en format XML
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Kinin Receptors</title>
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<series><title level="j">Hypertension</title>
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<front><div type="abstract" xml:lang="en"><p id="P1">We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I– converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B<sub>2</sub>
receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B<sub>2</sub>
receptors coupled to green fluorescent protein (B<sub>2</sub>
GFP) or to express only coupled B<sub>2</sub>
GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B<sub>2</sub>
receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18× slower than Ang I and ≈30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although μmol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B<sub>2</sub>
GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B<sub>2</sub>
receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-α, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B<sub>2</sub>
activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B<sub>2</sub>
receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">7906255</journal-id>
<journal-id journal-id-type="pubmed-jr-id">4217</journal-id>
<journal-id journal-id-type="nlm-ta">Hypertension</journal-id>
<journal-title>Hypertension</journal-title>
<issn pub-type="ppub">0194-911X</issn>
<issn pub-type="epub">1524-4563</issn>
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<article-id pub-id-type="manuscript">NIHMS6405</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Hydrolysis of Angiotensin Peptides by Human Angiotensin I–Converting Enzyme and the Resensitization of B<sub>2</sub>
Kinin Receptors</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Zhenlong</given-names>
</name>
</contrib>
<aff id="A1">From the Department of Pharmacology, University of Illinois College of Medicine, Chicago.</aff>
</contrib-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tan</surname>
<given-names>Fulong</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Erdös</surname>
<given-names>Ervin G.</given-names>
</name>
</contrib>
<aff id="A2">From the Departments of Pharmacology and Anesthesiology, University of Illinois College of Medicine, Chicago.</aff>
</contrib-group>
<contrib-group><contrib contrib-type="author"><name><surname>Deddish</surname>
<given-names>Peter A.</given-names>
</name>
</contrib>
<aff id="A3">From the Departments of Pharmacology, Anatomy and Cell Biology, University of Illinois College of Medicine, Chicago.</aff>
</contrib-group>
<author-notes><corresp id="CR1">Correspondence to Ervin G. Erdös, MD, Professor, Department of Pharmacology, 835 S Wolcott (MC 868), Chicago, IL 60612. E-mail <email>EGErdos@uic.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>5</day>
<month>9</month>
<year>2006</year>
</pub-date>
<pub-date pub-type="epub"><day>24</day>
<month>10</month>
<year>2005</year>
</pub-date>
<pub-date pub-type="ppub"><month>12</month>
<year>2005</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>13</day>
<month>9</month>
<year>2006</year>
</pub-date>
<volume>46</volume>
<issue>6</issue>
<fpage>1368</fpage>
<lpage>1373</lpage>
<abstract><p id="P1">We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I– converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B<sub>2</sub>
receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B<sub>2</sub>
receptors coupled to green fluorescent protein (B<sub>2</sub>
GFP) or to express only coupled B<sub>2</sub>
GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B<sub>2</sub>
receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18× slower than Ang I and ≈30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although μmol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B<sub>2</sub>
GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B<sub>2</sub>
receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-α, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B<sub>2</sub>
activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B<sub>2</sub>
receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.</p>
</abstract>
<kwd-group><kwd>angiotensin</kwd>
<kwd>angiotensin-converting enzyme</kwd>
<kwd>bradykinin</kwd>
<kwd>enalapril</kwd>
<kwd>protein kinases</kwd>
</kwd-group>
<contract-num rid="HL1">R01 HL068580-04</contract-num>
<contract-num rid="HL1">R01 HL068580-03</contract-num>
<contract-num rid="HL1">R01 HL068580-02</contract-num>
<contract-num rid="HL1">R01 HL068580-01</contract-num>
<contract-num rid="HL1">R01 HL036473-20</contract-num>
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<contract-sponsor id="HL1">National Heart, Lung, and Blood Institute : NHLBI</contract-sponsor>
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