PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2
Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adr...
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| Veröffentlicht in: | Journal of molecular and cellular cardiology 2022-11, Vol.172, p.63-77 |
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| creator | Fu, Jing Li, Li Chen, Long Su, Congping Feng, Xiuling Huang, Kai Zhang, Laxi Yang, Xiaoyan Fu, Qin |
| description | Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.
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•Ventricular myocytes are important source of TGF-β1 in chronic Isoproterenol (ISO)-induced heart failure.•TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts promotes cardiac hypertrophy and fibrosis.•PGE2 reverses ISO-induced heart failure by inhibiting TGF-β1 secretion from cardiomyocytes.•PGE2 reverses ISO-induced heart failure by disrupting TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis. |
| doi_str_mv | 10.1016/j.yjmcc.2022.07.012 |
| format | Article |
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[Display omitted]
•Ventricular myocytes are important source of TGF-β1 in chronic Isoproterenol (ISO)-induced heart failure.•TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts promotes cardiac hypertrophy and fibrosis.•PGE2 reverses ISO-induced heart failure by inhibiting TGF-β1 secretion from cardiomyocytes.•PGE2 reverses ISO-induced heart failure by disrupting TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.</description><identifier>ISSN: 0022-2828</identifier><identifier>ISSN: 1095-8584</identifier><identifier>EISSN: 1095-8584</identifier><identifier>DOI: 10.1016/j.yjmcc.2022.07.012</identifier><identifier>PMID: 35934102</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Dinoprostone ; Fibrosis ; GRK2 ; Heart Diseases - pathology ; Heart Failure ; Isoproterenol - pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac - pathology ; PGE2 ; Remodeling ; TGF-β1 ; Transforming Growth Factor beta1 ; β adrenergic signaling</subject><ispartof>Journal of molecular and cellular cardiology, 2022-11, Vol.172, p.63-77</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright © 2022 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c274t-aa3d62ffaeda2408c903c7db92de0d00028a0250ee703906c31b4409dbfafb223</citedby><cites>FETCH-LOGICAL-c274t-aa3d62ffaeda2408c903c7db92de0d00028a0250ee703906c31b4409dbfafb223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.yjmcc.2022.07.012$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35934102$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fu, Jing</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Chen, Long</creatorcontrib><creatorcontrib>Su, Congping</creatorcontrib><creatorcontrib>Feng, Xiuling</creatorcontrib><creatorcontrib>Huang, Kai</creatorcontrib><creatorcontrib>Zhang, Laxi</creatorcontrib><creatorcontrib>Yang, Xiaoyan</creatorcontrib><creatorcontrib>Fu, Qin</creatorcontrib><title>PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2</title><title>Journal of molecular and cellular cardiology</title><addtitle>J Mol Cell Cardiol</addtitle><description>Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.
[Display omitted]
•Ventricular myocytes are important source of TGF-β1 in chronic Isoproterenol (ISO)-induced heart failure.•TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts promotes cardiac hypertrophy and fibrosis.•PGE2 reverses ISO-induced heart failure by inhibiting TGF-β1 secretion from cardiomyocytes.•PGE2 reverses ISO-induced heart failure by disrupting TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.</description><subject>Animals</subject><subject>Dinoprostone</subject><subject>Fibrosis</subject><subject>GRK2</subject><subject>Heart Diseases - pathology</subject><subject>Heart Failure</subject><subject>Isoproterenol - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myocytes, Cardiac - pathology</subject><subject>PGE2</subject><subject>Remodeling</subject><subject>TGF-β1</subject><subject>Transforming Growth Factor beta1</subject><subject>β adrenergic signaling</subject><issn>0022-2828</issn><issn>1095-8584</issn><issn>1095-8584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u1DAUhS1URIfCEyAhL7tJuLaTSbzooqraAVEJhMracuybiYf8tLbTKkteiQfhmfB0Spdd3cU55957PkI-MMgZsPWnXb7sBmNyDpznUOXA-CuyYiDLrC7r4oisICkZr3l9TN6GsAMAWQjxhhyLUoqCAV-R3983l5ze-imiiYHqrXZjiLRD7SNttetnjzR2fpq3HXVj5xoX3bilN5ur7O8fRsMyxg6DC0mkRnvrpmGZzBIxLRstNX4KIer-F20wPiCOz8m9uvnxlb8jr1vdB3z_NE_Iz6vLm4vP2fW3zZeL8-vM8KqImdbCrnnbarSaF1AbCcJUtpHcIthUjdcaeAmIFQgJayNYUxQgbdPqtuFcnJDTw95U9m7GENXggsG-1yNOc1B8LaUsK1btreJgffzeY6tuvRu0XxQDtWevduqRvdqzV1CpxD6lPj4dmJsB7XPmP-xkODsYMNW8d-hVMA5Hg9b5RF_Zyb144B9jd5h5</recordid><startdate>202211</startdate><enddate>202211</enddate><creator>Fu, Jing</creator><creator>Li, Li</creator><creator>Chen, Long</creator><creator>Su, Congping</creator><creator>Feng, Xiuling</creator><creator>Huang, Kai</creator><creator>Zhang, Laxi</creator><creator>Yang, Xiaoyan</creator><creator>Fu, Qin</creator><general>Elsevier Ltd</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>202211</creationdate><title>PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2</title><author>Fu, Jing ; Li, Li ; Chen, Long ; Su, Congping ; Feng, Xiuling ; Huang, Kai ; Zhang, Laxi ; Yang, Xiaoyan ; Fu, Qin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c274t-aa3d62ffaeda2408c903c7db92de0d00028a0250ee703906c31b4409dbfafb223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Dinoprostone</topic><topic>Fibrosis</topic><topic>GRK2</topic><topic>Heart Diseases - pathology</topic><topic>Heart Failure</topic><topic>Isoproterenol - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myocytes, Cardiac - pathology</topic><topic>PGE2</topic><topic>Remodeling</topic><topic>TGF-β1</topic><topic>Transforming Growth Factor beta1</topic><topic>β adrenergic signaling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fu, Jing</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Chen, Long</creatorcontrib><creatorcontrib>Su, Congping</creatorcontrib><creatorcontrib>Feng, Xiuling</creatorcontrib><creatorcontrib>Huang, Kai</creatorcontrib><creatorcontrib>Zhang, Laxi</creatorcontrib><creatorcontrib>Yang, Xiaoyan</creatorcontrib><creatorcontrib>Fu, Qin</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>Journal of molecular and cellular cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fu, Jing</au><au>Li, Li</au><au>Chen, Long</au><au>Su, Congping</au><au>Feng, Xiuling</au><au>Huang, Kai</au><au>Zhang, Laxi</au><au>Yang, Xiaoyan</au><au>Fu, Qin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2</atitle><jtitle>Journal of molecular and cellular cardiology</jtitle><addtitle>J Mol Cell Cardiol</addtitle><date>2022-11</date><risdate>2022</risdate><volume>172</volume><spage>63</spage><epage>77</epage><pages>63-77</pages><issn>0022-2828</issn><issn>1095-8584</issn><eissn>1095-8584</eissn><abstract>Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.
[Display omitted]
•Ventricular myocytes are important source of TGF-β1 in chronic Isoproterenol (ISO)-induced heart failure.•TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts promotes cardiac hypertrophy and fibrosis.•PGE2 reverses ISO-induced heart failure by inhibiting TGF-β1 secretion from cardiomyocytes.•PGE2 reverses ISO-induced heart failure by disrupting TGF-β1-GRK2 crosstalk in cardiomyocytes and cardiac fibroblasts.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.•GRK2 inhibitor paroxetine ameliorates ISO-induced cardiac hypertrophy and fibrosis.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35934102</pmid><doi>10.1016/j.yjmcc.2022.07.012</doi><tpages>15</tpages></addata></record> |
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| subjects | Animals Dinoprostone Fibrosis GRK2 Heart Diseases - pathology Heart Failure Isoproterenol - pharmacology Male Mice Mice, Inbred C57BL Myocytes, Cardiac - pathology PGE2 Remodeling TGF-β1 Transforming Growth Factor beta1 β adrenergic signaling |
| title | PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2 |
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