Cardiovascular effects of a PEGylated apelin
► N-terminal conjugated 40kDa PEG apelin-36 was successfully produced. ► PEGylation had minimal effect on APJ receptor binding affinity. ► Comparable in vitro bioactivity was observed between PEG–apelin-36 and apelin-36. ► Inotropic effect and circulation time were prolonged with PEG–apelin-36. ► Ap...
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| Veröffentlicht in: | Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2012-11, Vol.38 (1), p.181-188 |
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| creator | Jia, Z.Q. Hou, L. Leger, A. Wu, I. Kudej, A.B. Stefano, J. Jiang, C. Pan, C.Q. Akita, G.Y. |
| description | ► N-terminal conjugated 40kDa PEG apelin-36 was successfully produced. ► PEGylation had minimal effect on APJ receptor binding affinity. ► Comparable in vitro bioactivity was observed between PEG–apelin-36 and apelin-36. ► Inotropic effect and circulation time were prolonged with PEG–apelin-36. ► Apelin-36 and PEG–apelin-36 had no effect on blood pressure.
Several studies have documented cardiovascular effects of apelin, including enhanced inotropy and vasodilation. However, these cardiovascular effects are short lived due to the predicted short circulating half-life of the apelin peptide. To address this limitation of apelin, we pursued N-terminal PEGylation of apelin and examined the cardiovascular effects of the PEGylated apelin. A 40kDa PEG conjugated apelin-36 (PEG–apelin-36) was successfully produced with N-terminal conjugation, high purity (>98%) and minimum reduction of APJ receptor binding affinity. Using an adenylate cyclase inhibition assay, comparable in vitro bioactivity was observed between the PEG–apelin-36 and unmodified apelin-36. In vivo evaluation of the PEG–apelin-36 was performed in normal rats and rats with myocardial infarction (MI). Cardiac function was assessed via echocardiography before, during a 20min IV infusion and up to 100min post peptide infusion. Similar increases in cardiac ejection fraction (EF) were observed during the infusion of PEG–apelin-36 and apelin-36 in normal rats. However, animals that received PEG–apelin-36 maintained significantly increased EF over the 100min post infusion monitoring period compared to the animals that received unmodified apelin-36. Interestingly, EF increases observed with PEG–apelin-36 and apelin-36 were greater in the MI rats. PEG–apelin-36 had a prolonged circulating life compared to apelin-36 in rats. There were no changes in aortic blood pressure when PEG–apelin-36 or apelin-36 was administered. To our knowledge this is the first report of apelin PEGylation and documentation of its cardiovascular effects. |
| doi_str_mv | 10.1016/j.peptides.2012.09.003 |
| format | Article |
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Several studies have documented cardiovascular effects of apelin, including enhanced inotropy and vasodilation. However, these cardiovascular effects are short lived due to the predicted short circulating half-life of the apelin peptide. To address this limitation of apelin, we pursued N-terminal PEGylation of apelin and examined the cardiovascular effects of the PEGylated apelin. A 40kDa PEG conjugated apelin-36 (PEG–apelin-36) was successfully produced with N-terminal conjugation, high purity (>98%) and minimum reduction of APJ receptor binding affinity. Using an adenylate cyclase inhibition assay, comparable in vitro bioactivity was observed between the PEG–apelin-36 and unmodified apelin-36. In vivo evaluation of the PEG–apelin-36 was performed in normal rats and rats with myocardial infarction (MI). Cardiac function was assessed via echocardiography before, during a 20min IV infusion and up to 100min post peptide infusion. Similar increases in cardiac ejection fraction (EF) were observed during the infusion of PEG–apelin-36 and apelin-36 in normal rats. However, animals that received PEG–apelin-36 maintained significantly increased EF over the 100min post infusion monitoring period compared to the animals that received unmodified apelin-36. Interestingly, EF increases observed with PEG–apelin-36 and apelin-36 were greater in the MI rats. PEG–apelin-36 had a prolonged circulating life compared to apelin-36 in rats. There were no changes in aortic blood pressure when PEG–apelin-36 or apelin-36 was administered. To our knowledge this is the first report of apelin PEGylation and documentation of its cardiovascular effects.</description><identifier>ISSN: 0196-9781</identifier><identifier>EISSN: 1873-5169</identifier><identifier>DOI: 10.1016/j.peptides.2012.09.003</identifier><identifier>PMID: 22986020</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>adenylate cyclase ; Administration, Intravenous ; Animals ; Apelin ; Apelin Receptors ; Arterial Pressure - drug effects ; binding capacity ; blood pressure ; Blood Pressure - drug effects ; Cardiac function ; cardiac output ; Cardiovascular System - drug effects ; Cell Line ; chemical bonding ; Echocardiography ; Female ; Half-Life ; Humans ; in vivo studies ; Inotropic effect ; Intercellular Signaling Peptides and Proteins - chemistry ; Intercellular Signaling Peptides and Proteins - pharmacokinetics ; Intercellular Signaling Peptides and Proteins - pharmacology ; Male ; monitoring ; myocardial infarction ; Myocardial Infarction - drug therapy ; PEGylation ; Polyethylene Glycols - chemistry ; Rat ; Rats ; Rats, Inbred Lew ; Receptors, G-Protein-Coupled - metabolism ; vasodilation</subject><ispartof>Peptides (New York, N.Y. : 1980), 2012-11, Vol.38 (1), p.181-188</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-754376174d462a4798041d181b7ba338d8867ef1a2f9921620c3cbf2236eb9623</citedby><cites>FETCH-LOGICAL-c392t-754376174d462a4798041d181b7ba338d8867ef1a2f9921620c3cbf2236eb9623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.peptides.2012.09.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22986020$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jia, Z.Q.</creatorcontrib><creatorcontrib>Hou, L.</creatorcontrib><creatorcontrib>Leger, A.</creatorcontrib><creatorcontrib>Wu, I.</creatorcontrib><creatorcontrib>Kudej, A.B.</creatorcontrib><creatorcontrib>Stefano, J.</creatorcontrib><creatorcontrib>Jiang, C.</creatorcontrib><creatorcontrib>Pan, C.Q.</creatorcontrib><creatorcontrib>Akita, G.Y.</creatorcontrib><title>Cardiovascular effects of a PEGylated apelin</title><title>Peptides (New York, N.Y. : 1980)</title><addtitle>Peptides</addtitle><description>► N-terminal conjugated 40kDa PEG apelin-36 was successfully produced. ► PEGylation had minimal effect on APJ receptor binding affinity. ► Comparable in vitro bioactivity was observed between PEG–apelin-36 and apelin-36. ► Inotropic effect and circulation time were prolonged with PEG–apelin-36. ► Apelin-36 and PEG–apelin-36 had no effect on blood pressure.
Several studies have documented cardiovascular effects of apelin, including enhanced inotropy and vasodilation. However, these cardiovascular effects are short lived due to the predicted short circulating half-life of the apelin peptide. To address this limitation of apelin, we pursued N-terminal PEGylation of apelin and examined the cardiovascular effects of the PEGylated apelin. A 40kDa PEG conjugated apelin-36 (PEG–apelin-36) was successfully produced with N-terminal conjugation, high purity (>98%) and minimum reduction of APJ receptor binding affinity. Using an adenylate cyclase inhibition assay, comparable in vitro bioactivity was observed between the PEG–apelin-36 and unmodified apelin-36. In vivo evaluation of the PEG–apelin-36 was performed in normal rats and rats with myocardial infarction (MI). Cardiac function was assessed via echocardiography before, during a 20min IV infusion and up to 100min post peptide infusion. Similar increases in cardiac ejection fraction (EF) were observed during the infusion of PEG–apelin-36 and apelin-36 in normal rats. However, animals that received PEG–apelin-36 maintained significantly increased EF over the 100min post infusion monitoring period compared to the animals that received unmodified apelin-36. Interestingly, EF increases observed with PEG–apelin-36 and apelin-36 were greater in the MI rats. PEG–apelin-36 had a prolonged circulating life compared to apelin-36 in rats. There were no changes in aortic blood pressure when PEG–apelin-36 or apelin-36 was administered. To our knowledge this is the first report of apelin PEGylation and documentation of its cardiovascular effects.</description><subject>adenylate cyclase</subject><subject>Administration, Intravenous</subject><subject>Animals</subject><subject>Apelin</subject><subject>Apelin Receptors</subject><subject>Arterial Pressure - drug effects</subject><subject>binding capacity</subject><subject>blood pressure</subject><subject>Blood Pressure - drug effects</subject><subject>Cardiac function</subject><subject>cardiac output</subject><subject>Cardiovascular System - drug effects</subject><subject>Cell Line</subject><subject>chemical bonding</subject><subject>Echocardiography</subject><subject>Female</subject><subject>Half-Life</subject><subject>Humans</subject><subject>in vivo studies</subject><subject>Inotropic effect</subject><subject>Intercellular Signaling Peptides and Proteins - chemistry</subject><subject>Intercellular Signaling Peptides and Proteins - pharmacokinetics</subject><subject>Intercellular Signaling Peptides and Proteins - pharmacology</subject><subject>Male</subject><subject>monitoring</subject><subject>myocardial infarction</subject><subject>Myocardial Infarction - drug therapy</subject><subject>PEGylation</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Rat</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>vasodilation</subject><issn>0196-9781</issn><issn>1873-5169</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1P3DAQgGELUcEW-AuQYw8knbGz_ri1WgGthNRKhbPl2GPkVXYT7CwS_56sFnrl5Ms7M9bD2CVCg4Dy-7oZaZxSoNJwQN6AaQDEEVugVqJeojTHbAFoZG2UxlP2tZQ1ALSt0SfslHOjJXBYsOuVyyENL674Xe9yRTGSn0o1xMpVf2_uXns3UajcSH3anrMv0fWFLt7fM_Z4e_Ow-lXf_7n7vfp5X3th-FSrZSuURNWGVnLXKqOhxYAaO9U5IXTQWiqK6Hg0hqPk4IXvIudCUmckF2fs22HvmIfnHZXJblLx1PduS8OuWMQlKlBSqTmVh9TnoZRM0Y45bVx-tQh2L2XX9kPK7qUsGDtLzYOX7zd23YbC_7EPmjm4OgTRDdY95VTs4795g5wZQS9xX_w4FDRbvCTKtvhEW08h5RnRhiF99os3M2mDuA</recordid><startdate>20121101</startdate><enddate>20121101</enddate><creator>Jia, Z.Q.</creator><creator>Hou, L.</creator><creator>Leger, A.</creator><creator>Wu, I.</creator><creator>Kudej, A.B.</creator><creator>Stefano, J.</creator><creator>Jiang, C.</creator><creator>Pan, C.Q.</creator><creator>Akita, G.Y.</creator><general>Elsevier Inc</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20121101</creationdate><title>Cardiovascular effects of a PEGylated apelin</title><author>Jia, Z.Q. ; Hou, L. ; Leger, A. ; Wu, I. ; Kudej, A.B. ; Stefano, J. ; Jiang, C. ; Pan, C.Q. ; Akita, G.Y.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-754376174d462a4798041d181b7ba338d8867ef1a2f9921620c3cbf2236eb9623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>adenylate cyclase</topic><topic>Administration, Intravenous</topic><topic>Animals</topic><topic>Apelin</topic><topic>Apelin Receptors</topic><topic>Arterial Pressure - drug effects</topic><topic>binding capacity</topic><topic>blood pressure</topic><topic>Blood Pressure - drug effects</topic><topic>Cardiac function</topic><topic>cardiac output</topic><topic>Cardiovascular System - drug effects</topic><topic>Cell Line</topic><topic>chemical bonding</topic><topic>Echocardiography</topic><topic>Female</topic><topic>Half-Life</topic><topic>Humans</topic><topic>in vivo studies</topic><topic>Inotropic effect</topic><topic>Intercellular Signaling Peptides and Proteins - chemistry</topic><topic>Intercellular Signaling Peptides and Proteins - pharmacokinetics</topic><topic>Intercellular Signaling Peptides and Proteins - pharmacology</topic><topic>Male</topic><topic>monitoring</topic><topic>myocardial infarction</topic><topic>Myocardial Infarction - drug therapy</topic><topic>PEGylation</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Rat</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>vasodilation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jia, Z.Q.</creatorcontrib><creatorcontrib>Hou, L.</creatorcontrib><creatorcontrib>Leger, A.</creatorcontrib><creatorcontrib>Wu, I.</creatorcontrib><creatorcontrib>Kudej, A.B.</creatorcontrib><creatorcontrib>Stefano, J.</creatorcontrib><creatorcontrib>Jiang, C.</creatorcontrib><creatorcontrib>Pan, C.Q.</creatorcontrib><creatorcontrib>Akita, G.Y.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Peptides (New York, N.Y. : 1980)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jia, Z.Q.</au><au>Hou, L.</au><au>Leger, A.</au><au>Wu, I.</au><au>Kudej, A.B.</au><au>Stefano, J.</au><au>Jiang, C.</au><au>Pan, C.Q.</au><au>Akita, G.Y.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cardiovascular effects of a PEGylated apelin</atitle><jtitle>Peptides (New York, N.Y. : 1980)</jtitle><addtitle>Peptides</addtitle><date>2012-11-01</date><risdate>2012</risdate><volume>38</volume><issue>1</issue><spage>181</spage><epage>188</epage><pages>181-188</pages><issn>0196-9781</issn><eissn>1873-5169</eissn><abstract>► N-terminal conjugated 40kDa PEG apelin-36 was successfully produced. ► PEGylation had minimal effect on APJ receptor binding affinity. ► Comparable in vitro bioactivity was observed between PEG–apelin-36 and apelin-36. ► Inotropic effect and circulation time were prolonged with PEG–apelin-36. ► Apelin-36 and PEG–apelin-36 had no effect on blood pressure.
Several studies have documented cardiovascular effects of apelin, including enhanced inotropy and vasodilation. However, these cardiovascular effects are short lived due to the predicted short circulating half-life of the apelin peptide. To address this limitation of apelin, we pursued N-terminal PEGylation of apelin and examined the cardiovascular effects of the PEGylated apelin. A 40kDa PEG conjugated apelin-36 (PEG–apelin-36) was successfully produced with N-terminal conjugation, high purity (>98%) and minimum reduction of APJ receptor binding affinity. Using an adenylate cyclase inhibition assay, comparable in vitro bioactivity was observed between the PEG–apelin-36 and unmodified apelin-36. In vivo evaluation of the PEG–apelin-36 was performed in normal rats and rats with myocardial infarction (MI). Cardiac function was assessed via echocardiography before, during a 20min IV infusion and up to 100min post peptide infusion. Similar increases in cardiac ejection fraction (EF) were observed during the infusion of PEG–apelin-36 and apelin-36 in normal rats. However, animals that received PEG–apelin-36 maintained significantly increased EF over the 100min post infusion monitoring period compared to the animals that received unmodified apelin-36. Interestingly, EF increases observed with PEG–apelin-36 and apelin-36 were greater in the MI rats. PEG–apelin-36 had a prolonged circulating life compared to apelin-36 in rats. There were no changes in aortic blood pressure when PEG–apelin-36 or apelin-36 was administered. To our knowledge this is the first report of apelin PEGylation and documentation of its cardiovascular effects.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22986020</pmid><doi>10.1016/j.peptides.2012.09.003</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0196-9781 |
| ispartof | Peptides (New York, N.Y. : 1980), 2012-11, Vol.38 (1), p.181-188 |
| issn | 0196-9781 1873-5169 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | adenylate cyclase Administration, Intravenous Animals Apelin Apelin Receptors Arterial Pressure - drug effects binding capacity blood pressure Blood Pressure - drug effects Cardiac function cardiac output Cardiovascular System - drug effects Cell Line chemical bonding Echocardiography Female Half-Life Humans in vivo studies Inotropic effect Intercellular Signaling Peptides and Proteins - chemistry Intercellular Signaling Peptides and Proteins - pharmacokinetics Intercellular Signaling Peptides and Proteins - pharmacology Male monitoring myocardial infarction Myocardial Infarction - drug therapy PEGylation Polyethylene Glycols - chemistry Rat Rats Rats, Inbred Lew Receptors, G-Protein-Coupled - metabolism vasodilation |
| title | Cardiovascular effects of a PEGylated apelin |
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