Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm
Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibitio...
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| Veröffentlicht in: | Scientific reports 2019-09, Vol.9 (1), p.13458-13, Article 13458 |
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| creator | Sharma, Neekun Dev, Rishabh Ruiz-Rosado, Juan de Dios Partida-Sanchez, Santiago Guerau-de-Arellano, Mireia Dhakal, Pramod Kuivaniemi, Helena Hans, Chetan P. |
| description | Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P |
| doi_str_mv | 10.1038/s41598-019-49682-0 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6748927</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2292054915</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-d6757540ac0239460ccc3d465a42327c40564597aafcd1269d3ab5f1756b00c33</originalsourceid><addsrcrecordid>eNp9kUtLxDAUhYMojoz-ARcScF3Ns202gogvEHWh63Cbpm2kbcakI8y_Nzo66sZsErjnnntPPoQOKTmhhJenUVCpyoxQlQmVlywjW2iPESEzxhnb_vWeoYMYX0g6kilB1S6acSo5KTnfQ_DYQRjA-N63zkCP3di5yk3Oj9g3-N5PpsPRtSP0bmxxsG2wMdqIF8FmNk5Q9S52tsZQ1X5wSYbBh8kZDKNdhlUc9tFOA320B1_3HD1fXT5d3GR3D9e3F-d3mRGFmLI6L2QhBQFDGFciJ8YYXotcgkghCiOIzIVUBUBjaspyVXOoZEMLmVeEGM7n6Gztu1hWg62NHacAvV4EN0BYaQ9O_62MrtOtf9N5IUrFimRw_GUQ_OsyZdMvfhlSoqgZU4xIodK3zRFbq0zwMQbbbCZQoj_I6DUZncjoTzKapKaj37ttWr45JAFfC2Iqja0NP7P_sX0HTbabGQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2292054915</pqid></control><display><type>article</type><title>Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><source>Springer Nature OA Free Journals</source><creator>Sharma, Neekun ; Dev, Rishabh ; Ruiz-Rosado, Juan de Dios ; Partida-Sanchez, Santiago ; Guerau-de-Arellano, Mireia ; Dhakal, Pramod ; Kuivaniemi, Helena ; Hans, Chetan P.</creator><creatorcontrib>Sharma, Neekun ; Dev, Rishabh ; Ruiz-Rosado, Juan de Dios ; Partida-Sanchez, Santiago ; Guerau-de-Arellano, Mireia ; Dhakal, Pramod ; Kuivaniemi, Helena ; Hans, Chetan P.</creatorcontrib><description>Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated
Apoe
−/−
mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of
Apoe
−/−
mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R
2
= 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-49682-0</identifier><identifier>PMID: 31530833</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/21 ; 13/31 ; 13/51 ; 64/110 ; 692/699/75/593/1287 ; 692/699/75/593/2724 ; 96/1 ; ADP-ribosyl Cyclase 1 - metabolism ; Aneurysms ; Angiotensin ; Angiotensin II ; Angiotensin II - adverse effects ; Animals ; Aorta - drug effects ; Aorta - metabolism ; Aortic Aneurysm, Abdominal - chemically induced ; Aortic Aneurysm, Abdominal - diagnostic imaging ; Aortic Aneurysm, Abdominal - drug therapy ; Aortic Aneurysm, Abdominal - metabolism ; Aortic aneurysms ; Apolipoprotein E ; CD38 antigen ; Cells, Cultured ; Collagen ; Collagen - metabolism ; Cytokines - metabolism ; Dipeptides - pharmacology ; Disease Models, Animal ; Elastin ; Extracellular Matrix - drug effects ; Extracellular Matrix - metabolism ; Gene Expression Regulation - drug effects ; Humanities and Social Sciences ; Humans ; Immunoreactivity ; Inflammation ; Male ; Membrane Glycoproteins - metabolism ; Mice ; Microfibrils ; multidisciplinary ; Myeloid cells ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - metabolism ; Phenylglycine ; Proteolysis ; Receptors, Notch - antagonists & inhibitors ; Receptors, Notch - metabolism ; Science ; Science (multidisciplinary) ; Signal Transduction - drug effects ; Smooth muscle ; Therapeutic applications ; Wave velocity</subject><ispartof>Scientific reports, 2019-09, Vol.9 (1), p.13458-13, Article 13458</ispartof><rights>The Author(s) 2019</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-d6757540ac0239460ccc3d465a42327c40564597aafcd1269d3ab5f1756b00c33</citedby><cites>FETCH-LOGICAL-c474t-d6757540ac0239460ccc3d465a42327c40564597aafcd1269d3ab5f1756b00c33</cites><orcidid>0000-0003-2996-9440 ; 0000-0003-1830-9084 ; 0000-0001-5753-8766</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748927/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748927/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31530833$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sharma, Neekun</creatorcontrib><creatorcontrib>Dev, Rishabh</creatorcontrib><creatorcontrib>Ruiz-Rosado, Juan de Dios</creatorcontrib><creatorcontrib>Partida-Sanchez, Santiago</creatorcontrib><creatorcontrib>Guerau-de-Arellano, Mireia</creatorcontrib><creatorcontrib>Dhakal, Pramod</creatorcontrib><creatorcontrib>Kuivaniemi, Helena</creatorcontrib><creatorcontrib>Hans, Chetan P.</creatorcontrib><title>Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated
Apoe
−/−
mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of
Apoe
−/−
mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R
2
= 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.</description><subject>13/21</subject><subject>13/31</subject><subject>13/51</subject><subject>64/110</subject><subject>692/699/75/593/1287</subject><subject>692/699/75/593/2724</subject><subject>96/1</subject><subject>ADP-ribosyl Cyclase 1 - metabolism</subject><subject>Aneurysms</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - adverse effects</subject><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - metabolism</subject><subject>Aortic Aneurysm, Abdominal - chemically induced</subject><subject>Aortic Aneurysm, Abdominal - diagnostic imaging</subject><subject>Aortic Aneurysm, Abdominal - drug therapy</subject><subject>Aortic Aneurysm, Abdominal - metabolism</subject><subject>Aortic aneurysms</subject><subject>Apolipoprotein E</subject><subject>CD38 antigen</subject><subject>Cells, Cultured</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Cytokines - metabolism</subject><subject>Dipeptides - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Elastin</subject><subject>Extracellular Matrix - drug effects</subject><subject>Extracellular Matrix - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immunoreactivity</subject><subject>Inflammation</subject><subject>Male</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Mice</subject><subject>Microfibrils</subject><subject>multidisciplinary</subject><subject>Myeloid cells</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Phenylglycine</subject><subject>Proteolysis</subject><subject>Receptors, Notch - antagonists & inhibitors</subject><subject>Receptors, Notch - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction - drug effects</subject><subject>Smooth muscle</subject><subject>Therapeutic applications</subject><subject>Wave velocity</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kUtLxDAUhYMojoz-ARcScF3Ns202gogvEHWh63Cbpm2kbcakI8y_Nzo66sZsErjnnntPPoQOKTmhhJenUVCpyoxQlQmVlywjW2iPESEzxhnb_vWeoYMYX0g6kilB1S6acSo5KTnfQ_DYQRjA-N63zkCP3di5yk3Oj9g3-N5PpsPRtSP0bmxxsG2wMdqIF8FmNk5Q9S52tsZQ1X5wSYbBh8kZDKNdhlUc9tFOA320B1_3HD1fXT5d3GR3D9e3F-d3mRGFmLI6L2QhBQFDGFciJ8YYXotcgkghCiOIzIVUBUBjaspyVXOoZEMLmVeEGM7n6Gztu1hWg62NHacAvV4EN0BYaQ9O_62MrtOtf9N5IUrFimRw_GUQ_OsyZdMvfhlSoqgZU4xIodK3zRFbq0zwMQbbbCZQoj_I6DUZncjoTzKapKaj37ttWr45JAFfC2Iqja0NP7P_sX0HTbabGQ</recordid><startdate>20190917</startdate><enddate>20190917</enddate><creator>Sharma, Neekun</creator><creator>Dev, Rishabh</creator><creator>Ruiz-Rosado, Juan de Dios</creator><creator>Partida-Sanchez, Santiago</creator><creator>Guerau-de-Arellano, Mireia</creator><creator>Dhakal, Pramod</creator><creator>Kuivaniemi, Helena</creator><creator>Hans, Chetan P.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2996-9440</orcidid><orcidid>https://orcid.org/0000-0003-1830-9084</orcidid><orcidid>https://orcid.org/0000-0001-5753-8766</orcidid></search><sort><creationdate>20190917</creationdate><title>Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm</title><author>Sharma, Neekun ; Dev, Rishabh ; Ruiz-Rosado, Juan de Dios ; Partida-Sanchez, Santiago ; Guerau-de-Arellano, Mireia ; Dhakal, Pramod ; Kuivaniemi, Helena ; Hans, Chetan P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-d6757540ac0239460ccc3d465a42327c40564597aafcd1269d3ab5f1756b00c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/21</topic><topic>13/31</topic><topic>13/51</topic><topic>64/110</topic><topic>692/699/75/593/1287</topic><topic>692/699/75/593/2724</topic><topic>96/1</topic><topic>ADP-ribosyl Cyclase 1 - metabolism</topic><topic>Aneurysms</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensin II - adverse effects</topic><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - metabolism</topic><topic>Aortic Aneurysm, Abdominal - chemically induced</topic><topic>Aortic Aneurysm, Abdominal - diagnostic imaging</topic><topic>Aortic Aneurysm, Abdominal - drug therapy</topic><topic>Aortic Aneurysm, Abdominal - metabolism</topic><topic>Aortic aneurysms</topic><topic>Apolipoprotein E</topic><topic>CD38 antigen</topic><topic>Cells, Cultured</topic><topic>Collagen</topic><topic>Collagen - metabolism</topic><topic>Cytokines - metabolism</topic><topic>Dipeptides - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Elastin</topic><topic>Extracellular Matrix - drug effects</topic><topic>Extracellular Matrix - metabolism</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immunoreactivity</topic><topic>Inflammation</topic><topic>Male</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Mice</topic><topic>Microfibrils</topic><topic>multidisciplinary</topic><topic>Myeloid cells</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Phenylglycine</topic><topic>Proteolysis</topic><topic>Receptors, Notch - antagonists & inhibitors</topic><topic>Receptors, Notch - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal Transduction - drug effects</topic><topic>Smooth muscle</topic><topic>Therapeutic applications</topic><topic>Wave velocity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sharma, Neekun</creatorcontrib><creatorcontrib>Dev, Rishabh</creatorcontrib><creatorcontrib>Ruiz-Rosado, Juan de Dios</creatorcontrib><creatorcontrib>Partida-Sanchez, Santiago</creatorcontrib><creatorcontrib>Guerau-de-Arellano, Mireia</creatorcontrib><creatorcontrib>Dhakal, Pramod</creatorcontrib><creatorcontrib>Kuivaniemi, Helena</creatorcontrib><creatorcontrib>Hans, Chetan P.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sharma, Neekun</au><au>Dev, Rishabh</au><au>Ruiz-Rosado, Juan de Dios</au><au>Partida-Sanchez, Santiago</au><au>Guerau-de-Arellano, Mireia</au><au>Dhakal, Pramod</au><au>Kuivaniemi, Helena</au><au>Hans, Chetan P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-09-17</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>13458</spage><epage>13</epage><pages>13458-13</pages><artnum>13458</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated
Apoe
−/−
mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of
Apoe
−/−
mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R
2
= 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31530833</pmid><doi>10.1038/s41598-019-49682-0</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-2996-9440</orcidid><orcidid>https://orcid.org/0000-0003-1830-9084</orcidid><orcidid>https://orcid.org/0000-0001-5753-8766</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/21 13/31 13/51 64/110 692/699/75/593/1287 692/699/75/593/2724 96/1 ADP-ribosyl Cyclase 1 - metabolism Aneurysms Angiotensin Angiotensin II Angiotensin II - adverse effects Animals Aorta - drug effects Aorta - metabolism Aortic Aneurysm, Abdominal - chemically induced Aortic Aneurysm, Abdominal - diagnostic imaging Aortic Aneurysm, Abdominal - drug therapy Aortic Aneurysm, Abdominal - metabolism Aortic aneurysms Apolipoprotein E CD38 antigen Cells, Cultured Collagen Collagen - metabolism Cytokines - metabolism Dipeptides - pharmacology Disease Models, Animal Elastin Extracellular Matrix - drug effects Extracellular Matrix - metabolism Gene Expression Regulation - drug effects Humanities and Social Sciences Humans Immunoreactivity Inflammation Male Membrane Glycoproteins - metabolism Mice Microfibrils multidisciplinary Myeloid cells Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Phenylglycine Proteolysis Receptors, Notch - antagonists & inhibitors Receptors, Notch - metabolism Science Science (multidisciplinary) Signal Transduction - drug effects Smooth muscle Therapeutic applications Wave velocity |
| title | Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm |
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