Loading…

Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure

Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosi...

Full description

Saved in:
Bibliographic Details
Published in:Free radical biology & medicine 2024-03, Vol.214, p.206-218
Main Authors: Zhang, Qi-qiang, Chen, Qing-shan, Feng, Fei, Cao, Xiang, Chen, Xiao-fei, Zhang, Hai
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3
cites cdi_FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3
container_end_page 218
container_issue
container_start_page 206
container_title Free radical biology & medicine
container_volume 214
creator Zhang, Qi-qiang
Chen, Qing-shan
Feng, Fei
Cao, Xiang
Chen, Xiao-fei
Zhang, Hai
description Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2−/− mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2−/− mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure. [Display omitted] •This is the first finding that benzoylaconitine attenuates heart failure by inhibiting cardiac hypertrophy and fibrosis.•ACE2 was identified as a direct molecular target of benzoylaconitine by using limited proteolysis-mass spectrometry.•Benzoylaconitine targeting ACE2 regulates mitochondrial fission and inflammation to alleviate heart failure.
doi_str_mv 10.1016/j.freeradbiomed.2024.02.010
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2928586173</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S089158492400090X</els_id><sourcerecordid>2928586173</sourcerecordid><originalsourceid>FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3</originalsourceid><addsrcrecordid>eNqNkEtv3CAURlGVqpmm_QsVUjbd2L0YG3CymoymDylSN-0aYbieMPJAAnal9NeX0UwW3WWFdDn38R1CrhnUDJj4sq_HhJiMG3w8oKsbaNoamhoYvCErpiSv2q4XF2QFqmdVp9r-krzPeQ8AbcfVO3LJFRc9SLEi9g7D3_g8GRuDn33AG7qmjykefPZhR9ebbVPNJu1wRkfNrkB5pmNMFMODCfbIWJOcN5aOS7Czj4H6QB_QpMIZPy0JP5C3o5kyfjy_V-T31-2vzffq_ue3H5v1fWXLPXPVC5RMjYNTohMDt5axQXKAUmqMKzEGELIVvFNgpOhM65gcLY6dZUb2PfIr8vk0t9z_tGCedUlhcZpMwLhk3fSN6pRgkhf09oTaFHNOOOrH5A8mPWsG-mhZ7_V_lvXRsoZGF8ul-9N50TIc_156X7QWYHsCsMT94zHpbD0Gi84ntLN20b9q0T-AY5Zm</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2928586173</pqid></control><display><type>article</type><title>Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure</title><source>Elsevier:Jisc Collections:Elsevier Read and Publish Agreement 2022-2024:Freedom Collection (Reading list)</source><creator>Zhang, Qi-qiang ; Chen, Qing-shan ; Feng, Fei ; Cao, Xiang ; Chen, Xiao-fei ; Zhang, Hai</creator><creatorcontrib>Zhang, Qi-qiang ; Chen, Qing-shan ; Feng, Fei ; Cao, Xiang ; Chen, Xiao-fei ; Zhang, Hai</creatorcontrib><description>Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2−/− mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2−/− mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure. [Display omitted] •This is the first finding that benzoylaconitine attenuates heart failure by inhibiting cardiac hypertrophy and fibrosis.•ACE2 was identified as a direct molecular target of benzoylaconitine by using limited proteolysis-mass spectrometry.•Benzoylaconitine targeting ACE2 regulates mitochondrial fission and inflammation to alleviate heart failure.</description><identifier>ISSN: 0891-5849</identifier><identifier>EISSN: 1873-4596</identifier><identifier>DOI: 10.1016/j.freeradbiomed.2024.02.010</identifier><identifier>PMID: 38369076</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ACE2 ; Aconitine - analogs &amp; derivatives ; Angiotensin II - metabolism ; Angiotensin-Converting Enzyme 2 - genetics ; Animals ; Benzoylaconitine ; Cardiac remodeling ; Fibrosis ; Heart failure ; Heart Failure - drug therapy ; Heart Failure - genetics ; Hypertrophy ; Mice ; Mitochondrial ROS ; Myocytes, Cardiac - metabolism ; NF-kappa B - genetics ; NF-kappa B - metabolism ; NF-κB ; Peptidyl-Dipeptidase A - metabolism ; Rats ; Reactive Oxygen Species - metabolism</subject><ispartof>Free radical biology &amp; medicine, 2024-03, Vol.214, p.206-218</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3</citedby><cites>FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38369076$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Qi-qiang</creatorcontrib><creatorcontrib>Chen, Qing-shan</creatorcontrib><creatorcontrib>Feng, Fei</creatorcontrib><creatorcontrib>Cao, Xiang</creatorcontrib><creatorcontrib>Chen, Xiao-fei</creatorcontrib><creatorcontrib>Zhang, Hai</creatorcontrib><title>Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure</title><title>Free radical biology &amp; medicine</title><addtitle>Free Radic Biol Med</addtitle><description>Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2−/− mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2−/− mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure. [Display omitted] •This is the first finding that benzoylaconitine attenuates heart failure by inhibiting cardiac hypertrophy and fibrosis.•ACE2 was identified as a direct molecular target of benzoylaconitine by using limited proteolysis-mass spectrometry.•Benzoylaconitine targeting ACE2 regulates mitochondrial fission and inflammation to alleviate heart failure.</description><subject>ACE2</subject><subject>Aconitine - analogs &amp; derivatives</subject><subject>Angiotensin II - metabolism</subject><subject>Angiotensin-Converting Enzyme 2 - genetics</subject><subject>Animals</subject><subject>Benzoylaconitine</subject><subject>Cardiac remodeling</subject><subject>Fibrosis</subject><subject>Heart failure</subject><subject>Heart Failure - drug therapy</subject><subject>Heart Failure - genetics</subject><subject>Hypertrophy</subject><subject>Mice</subject><subject>Mitochondrial ROS</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>NF-kappa B - genetics</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB</subject><subject>Peptidyl-Dipeptidase A - metabolism</subject><subject>Rats</subject><subject>Reactive Oxygen Species - metabolism</subject><issn>0891-5849</issn><issn>1873-4596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqNkEtv3CAURlGVqpmm_QsVUjbd2L0YG3CymoymDylSN-0aYbieMPJAAnal9NeX0UwW3WWFdDn38R1CrhnUDJj4sq_HhJiMG3w8oKsbaNoamhoYvCErpiSv2q4XF2QFqmdVp9r-krzPeQ8AbcfVO3LJFRc9SLEi9g7D3_g8GRuDn33AG7qmjykefPZhR9ebbVPNJu1wRkfNrkB5pmNMFMODCfbIWJOcN5aOS7Czj4H6QB_QpMIZPy0JP5C3o5kyfjy_V-T31-2vzffq_ue3H5v1fWXLPXPVC5RMjYNTohMDt5axQXKAUmqMKzEGELIVvFNgpOhM65gcLY6dZUb2PfIr8vk0t9z_tGCedUlhcZpMwLhk3fSN6pRgkhf09oTaFHNOOOrH5A8mPWsG-mhZ7_V_lvXRsoZGF8ul-9N50TIc_156X7QWYHsCsMT94zHpbD0Gi84ntLN20b9q0T-AY5Zm</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Zhang, Qi-qiang</creator><creator>Chen, Qing-shan</creator><creator>Feng, Fei</creator><creator>Cao, Xiang</creator><creator>Chen, Xiao-fei</creator><creator>Zhang, Hai</creator><general>Elsevier Inc</general><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>202403</creationdate><title>Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure</title><author>Zhang, Qi-qiang ; Chen, Qing-shan ; Feng, Fei ; Cao, Xiang ; Chen, Xiao-fei ; Zhang, Hai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>ACE2</topic><topic>Aconitine - analogs &amp; derivatives</topic><topic>Angiotensin II - metabolism</topic><topic>Angiotensin-Converting Enzyme 2 - genetics</topic><topic>Animals</topic><topic>Benzoylaconitine</topic><topic>Cardiac remodeling</topic><topic>Fibrosis</topic><topic>Heart failure</topic><topic>Heart Failure - drug therapy</topic><topic>Heart Failure - genetics</topic><topic>Hypertrophy</topic><topic>Mice</topic><topic>Mitochondrial ROS</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>NF-kappa B - genetics</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB</topic><topic>Peptidyl-Dipeptidase A - metabolism</topic><topic>Rats</topic><topic>Reactive Oxygen Species - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Qi-qiang</creatorcontrib><creatorcontrib>Chen, Qing-shan</creatorcontrib><creatorcontrib>Feng, Fei</creatorcontrib><creatorcontrib>Cao, Xiang</creatorcontrib><creatorcontrib>Chen, Xiao-fei</creatorcontrib><creatorcontrib>Zhang, Hai</creatorcontrib><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>Free radical biology &amp; medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Qi-qiang</au><au>Chen, Qing-shan</au><au>Feng, Fei</au><au>Cao, Xiang</au><au>Chen, Xiao-fei</au><au>Zhang, Hai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure</atitle><jtitle>Free radical biology &amp; medicine</jtitle><addtitle>Free Radic Biol Med</addtitle><date>2024-03</date><risdate>2024</risdate><volume>214</volume><spage>206</spage><epage>218</epage><pages>206-218</pages><issn>0891-5849</issn><eissn>1873-4596</eissn><abstract>Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2−/− mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2−/− mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure. [Display omitted] •This is the first finding that benzoylaconitine attenuates heart failure by inhibiting cardiac hypertrophy and fibrosis.•ACE2 was identified as a direct molecular target of benzoylaconitine by using limited proteolysis-mass spectrometry.•Benzoylaconitine targeting ACE2 regulates mitochondrial fission and inflammation to alleviate heart failure.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38369076</pmid><doi>10.1016/j.freeradbiomed.2024.02.010</doi><tpages>13</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0891-5849
ispartof Free radical biology & medicine, 2024-03, Vol.214, p.206-218
issn 0891-5849
1873-4596
language eng
recordid cdi_proquest_miscellaneous_2928586173
source Elsevier:Jisc Collections:Elsevier Read and Publish Agreement 2022-2024:Freedom Collection (Reading list)
subjects ACE2
Aconitine - analogs & derivatives
Angiotensin II - metabolism
Angiotensin-Converting Enzyme 2 - genetics
Animals
Benzoylaconitine
Cardiac remodeling
Fibrosis
Heart failure
Heart Failure - drug therapy
Heart Failure - genetics
Hypertrophy
Mice
Mitochondrial ROS
Myocytes, Cardiac - metabolism
NF-kappa B - genetics
NF-kappa B - metabolism
NF-κB
Peptidyl-Dipeptidase A - metabolism
Rats
Reactive Oxygen Species - metabolism
title Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-22T13%3A46%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Benzoylaconitine:%20A%20promising%20ACE2-targeted%20agonist%20for%20enhancing%20cardiac%20function%20in%20heart%20failure&rft.jtitle=Free%20radical%20biology%20&%20medicine&rft.au=Zhang,%20Qi-qiang&rft.date=2024-03&rft.volume=214&rft.spage=206&rft.epage=218&rft.pages=206-218&rft.issn=0891-5849&rft.eissn=1873-4596&rft_id=info:doi/10.1016/j.freeradbiomed.2024.02.010&rft_dat=%3Cproquest_cross%3E2928586173%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c383t-96e718fbd8656b3cc11b73008fb2ad584b067463580a765a4d17fcef5c1a799e3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2928586173&rft_id=info:pmid/38369076&rfr_iscdi=true