Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways
Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2022-08, Vol.43 (8), p.1989-2002 |
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| container_title | Acta pharmacologica Sinica |
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| creator | Li, Dan Guo, Ying-ying Cen, Xian-feng Qiu, Hong-liang Chen, Si Zeng, Xiao-feng Zeng, Qian Xu, Man Tang, Qi-zhu |
| description | Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg
-1
· d
-1
, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling. |
| doi_str_mv | 10.1038/s41401-021-00820-3 |
| format | Article |
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-1
· d
-1
, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-021-00820-3</identifier><identifier>PMID: 34916609</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>1-Phosphatidylinositol 3-kinase ; Acids ; Agonists ; AKT protein ; Animals ; Aorta ; Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Cardiomegaly - drug therapy ; Cardiomegaly - metabolism ; Cardiomegaly - prevention & control ; Cardiomyocytes ; Cardiovascular diseases ; Cytokines ; Cytotoxicity ; Fibrosis ; Genes ; Herbal medicine ; Hypertrophy ; Immunology ; Inflammation ; Internal Medicine ; Kinases ; Laboratory animals ; Medical Microbiology ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac ; Neonates ; NF-kappa B - metabolism ; NF-κB protein ; Nuclear transport ; Oxidative stress ; Pentacyclic Triterpenes - pharmacology ; Pharmacology/Toxicology ; Phenylephrine ; Phosphatidylinositol 3-Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Signal Transduction ; TLR4 protein ; Toll-Like Receptor 4 - metabolism ; Toll-like receptors ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2022-08, Vol.43 (8), p.1989-2002</ispartof><rights>The Author(s), under exclusive licence to CPS and SIMM 2021</rights><rights>2021. The Author(s), under exclusive licence to CPS and SIMM.</rights><rights>The Author(s), under exclusive licence to CPS and SIMM 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-c29b5eb1d1b8e8639077cca7ebcf6d26be0ac68dea7ed954c3b74549c00f8a193</citedby><cites>FETCH-LOGICAL-c474t-c29b5eb1d1b8e8639077cca7ebcf6d26be0ac68dea7ed954c3b74549c00f8a193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343642/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343642/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,725,778,782,883,27907,27908,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34916609$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Guo, Ying-ying</creatorcontrib><creatorcontrib>Cen, Xian-feng</creatorcontrib><creatorcontrib>Qiu, Hong-liang</creatorcontrib><creatorcontrib>Chen, Si</creatorcontrib><creatorcontrib>Zeng, Xiao-feng</creatorcontrib><creatorcontrib>Zeng, Qian</creatorcontrib><creatorcontrib>Xu, Man</creatorcontrib><creatorcontrib>Tang, Qi-zhu</creatorcontrib><title>Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg
-1
· d
-1
, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Acids</subject><subject>Agonists</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Aorta</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cardiomegaly - drug therapy</subject><subject>Cardiomegaly - metabolism</subject><subject>Cardiomegaly - prevention & control</subject><subject>Cardiomyocytes</subject><subject>Cardiovascular diseases</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Fibrosis</subject><subject>Genes</subject><subject>Herbal medicine</subject><subject>Hypertrophy</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myocytes, Cardiac</subject><subject>Neonates</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nuclear transport</subject><subject>Oxidative stress</subject><subject>Pentacyclic Triterpenes - pharmacology</subject><subject>Pharmacology/Toxicology</subject><subject>Phenylephrine</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Signal Transduction</subject><subject>TLR4 protein</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Toll-like receptors</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1OGzEUhS1EVULoC7BAI7Hpxq3_xh5vkGhUCmr4EYK15fE4yYTJeLA9qfJqPESfCbdJU2DBwrqW73eP79EB4BCjLxjR4mtgmCEMEUkHFQRBugMGWLAcCpKz3XTnAkOGCroH9kOYI0QJxfIj2KNMYs6RHIDLcd9Z12Sdd9GaGDI91XUbYma0r2ptstmqsz56181W2bLW2d34lsGbC_oTnj5EeHUGfz99yzodZ7_0KhyADxPdBPtpU4fg_uz73egcjq9_XIxOx9AwwSI0RJa5LXGFy8IWnEokhDFa2NJMeEV4aZE2vKhseqpkzgwtkysmDUKTQmNJh-Bkrdv15cJWxrbR60Z1vl5ov1JO1-p1p61nauqWSlJGOSNJ4PNGwLvH3oaoFnUwtml0a10fFOEY8zwnUiT0-A06d71vk71ESS4F4kl0CMiaMt6F4O1kuwxG6k9aap2WSmmpv2kpmoaOXtrYjvyLJwF0DYTUaqfW___7Hdlnhvmgwg</recordid><startdate>20220801</startdate><enddate>20220801</enddate><creator>Li, Dan</creator><creator>Guo, Ying-ying</creator><creator>Cen, Xian-feng</creator><creator>Qiu, Hong-liang</creator><creator>Chen, Si</creator><creator>Zeng, Xiao-feng</creator><creator>Zeng, Qian</creator><creator>Xu, Man</creator><creator>Tang, Qi-zhu</creator><general>Springer Nature Singapore</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20220801</creationdate><title>Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways</title><author>Li, Dan ; Guo, Ying-ying ; Cen, Xian-feng ; Qiu, Hong-liang ; Chen, Si ; Zeng, Xiao-feng ; Zeng, Qian ; Xu, Man ; Tang, Qi-zhu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-c29b5eb1d1b8e8639077cca7ebcf6d26be0ac68dea7ed954c3b74549c00f8a193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Acids</topic><topic>Agonists</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Aorta</topic><topic>Apoptosis</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cardiomegaly - drug therapy</topic><topic>Cardiomegaly - metabolism</topic><topic>Cardiomegaly - prevention & control</topic><topic>Cardiomyocytes</topic><topic>Cardiovascular diseases</topic><topic>Cytokines</topic><topic>Cytotoxicity</topic><topic>Fibrosis</topic><topic>Genes</topic><topic>Herbal medicine</topic><topic>Hypertrophy</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myocytes, Cardiac</topic><topic>Neonates</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Nuclear transport</topic><topic>Oxidative stress</topic><topic>Pentacyclic Triterpenes - pharmacology</topic><topic>Pharmacology/Toxicology</topic><topic>Phenylephrine</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Signal Transduction</topic><topic>TLR4 protein</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Toll-like receptors</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Guo, Ying-ying</creatorcontrib><creatorcontrib>Cen, Xian-feng</creatorcontrib><creatorcontrib>Qiu, Hong-liang</creatorcontrib><creatorcontrib>Chen, Si</creatorcontrib><creatorcontrib>Zeng, Xiao-feng</creatorcontrib><creatorcontrib>Zeng, Qian</creatorcontrib><creatorcontrib>Xu, Man</creatorcontrib><creatorcontrib>Tang, Qi-zhu</creatorcontrib><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>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</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 Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</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>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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 China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Dan</au><au>Guo, Ying-ying</au><au>Cen, Xian-feng</au><au>Qiu, Hong-liang</au><au>Chen, Si</au><au>Zeng, Xiao-feng</au><au>Zeng, Qian</au><au>Xu, Man</au><au>Tang, Qi-zhu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2022-08-01</date><risdate>2022</risdate><volume>43</volume><issue>8</issue><spage>1989</spage><epage>2002</epage><pages>1989-2002</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg
-1
· d
-1
, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>34916609</pmid><doi>10.1038/s41401-021-00820-3</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase Acids Agonists AKT protein Animals Aorta Apoptosis Biomedical and Life Sciences Biomedicine Cardiomegaly - drug therapy Cardiomegaly - metabolism Cardiomegaly - prevention & control Cardiomyocytes Cardiovascular diseases Cytokines Cytotoxicity Fibrosis Genes Herbal medicine Hypertrophy Immunology Inflammation Internal Medicine Kinases Laboratory animals Medical Microbiology Mice Mice, Inbred C57BL Myocytes, Cardiac Neonates NF-kappa B - metabolism NF-κB protein Nuclear transport Oxidative stress Pentacyclic Triterpenes - pharmacology Pharmacology/Toxicology Phenylephrine Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Rats Signal Transduction TLR4 protein Toll-Like Receptor 4 - metabolism Toll-like receptors Vaccine |
| title | Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways |
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