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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...
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Published in: | Free radical biology & medicine 2024-03, Vol.214, p.206-218 |
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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 |
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[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 & 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 & 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 & 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 & 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 & 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 & 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 & 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> |
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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 |
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