Endothelin-1 upregulation mediates aging-related cardiac fibrosis

Abstract Endothelin-1 (ET-1) plays a major role in regulating myocardial fibrosis in several pathological conditions, such as hypertension and diabetes. Aging is an independent risk factor for myocardial fibrosis. We hypothesized that ET-1 upregulation may be a basis of enhanced collagen synthesis i...

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Veröffentlicht in:Journal of molecular and cellular cardiology 2015-03, Vol.80, p.101-109
Hauptverfasser: Wang, Xianwei, Guo, Zhikun, Ding, Zufeng, Khaidakov, Magomed, Lin, Juntang, Xu, Zhenping, Sharma, Shree G, Jiwani, Shahanawaz, Mehta, Jawahar L
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container_title Journal of molecular and cellular cardiology
container_volume 80
creator Wang, Xianwei
Guo, Zhikun
Ding, Zufeng
Khaidakov, Magomed
Lin, Juntang
Xu, Zhenping
Sharma, Shree G
Jiwani, Shahanawaz
Mehta, Jawahar L
description Abstract Endothelin-1 (ET-1) plays a major role in regulating myocardial fibrosis in several pathological conditions, such as hypertension and diabetes. Aging is an independent risk factor for myocardial fibrosis. We hypothesized that ET-1 upregulation may be a basis of enhanced collagen synthesis in the senescent fibroblasts resulting in cardiac fibrosis with aging. To examine this hypothesis, we cultured mouse cardiac fibroblasts to passage-30 (P30). β–Galactosidase activity and several other aging markers were markedly increased in P30 (vs. P3) fibroblasts, indicating that these cells were indeed undergoing senescence. Importantly, ET-1 expression was markedly upregulated in P30 (vs. P3) fibroblasts. Of note, estrogen receptor-α (ER-α), an important negative regulator of ET-1, was downregulated in P30 fibroblasts. We also studied aged (130-weeks old, female) mice hearts, and observed that ET-1 was upregulated and ER-α was downregulated in these hearts (vs. 6-week old mice hearts, female). Similar observations were made in the fibroblasts isolated from aged mice hearts. ET-1 upregulation with aging was also seen in ≈ 70-year old (vs. ≈ 30-year old) human heart sections. In concert with ET-1 upregulation, the expression of fibronectin and collagens was found to be markedly increased in P30 cardiac fibroblasts in culture, fibroblasts isolated from the aged mice hearts, and in aged human hearts. Interestingly, inhibition of ET-1 in the senescent P30 fibroblasts by 2 different strategies (the use of siRNA and the use of endothelin converting enzyme inhibitors) markedly suppressed expression of fibrosis signals. Further, treatment with synthetic ET-1 enhanced fibronectin and collagen expression in P3 cardiac fibroblasts. These observations in mice and human hearts suggest that aging-related cardiac fibrosis is, at least partially, dependent on the upregulation of ET-1.
doi_str_mv 10.1016/j.yjmcc.2015.01.001
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Aging is an independent risk factor for myocardial fibrosis. We hypothesized that ET-1 upregulation may be a basis of enhanced collagen synthesis in the senescent fibroblasts resulting in cardiac fibrosis with aging. To examine this hypothesis, we cultured mouse cardiac fibroblasts to passage-30 (P30). β–Galactosidase activity and several other aging markers were markedly increased in P30 (vs. P3) fibroblasts, indicating that these cells were indeed undergoing senescence. Importantly, ET-1 expression was markedly upregulated in P30 (vs. P3) fibroblasts. Of note, estrogen receptor-α (ER-α), an important negative regulator of ET-1, was downregulated in P30 fibroblasts. We also studied aged (130-weeks old, female) mice hearts, and observed that ET-1 was upregulated and ER-α was downregulated in these hearts (vs. 6-week old mice hearts, female). Similar observations were made in the fibroblasts isolated from aged mice hearts. ET-1 upregulation with aging was also seen in ≈ 70-year old (vs. ≈ 30-year old) human heart sections. In concert with ET-1 upregulation, the expression of fibronectin and collagens was found to be markedly increased in P30 cardiac fibroblasts in culture, fibroblasts isolated from the aged mice hearts, and in aged human hearts. Interestingly, inhibition of ET-1 in the senescent P30 fibroblasts by 2 different strategies (the use of siRNA and the use of endothelin converting enzyme inhibitors) markedly suppressed expression of fibrosis signals. Further, treatment with synthetic ET-1 enhanced fibronectin and collagen expression in P3 cardiac fibroblasts. These observations in mice and human hearts suggest that aging-related cardiac fibrosis is, at least partially, dependent on the upregulation of ET-1.</description><identifier>ISSN: 0022-2828</identifier><identifier>EISSN: 1095-8584</identifier><identifier>DOI: 10.1016/j.yjmcc.2015.01.001</identifier><identifier>PMID: 25584774</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aging ; Aging - genetics ; Animals ; Aspartic Acid Endopeptidases - antagonists &amp; inhibitors ; Aspartic Acid Endopeptidases - metabolism ; beta-Galactosidase - metabolism ; Cardiac fibrosis ; Cardiovascular ; Cellular Senescence - genetics ; Collagens ; Endothelin-1 ; Endothelin-1 - genetics ; Endothelin-1 - metabolism ; Endothelin-Converting Enzymes ; Enzyme Activation ; Estrogen Receptor alpha - genetics ; Estrogen Receptor alpha - metabolism ; Female ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibronectin ; Fibrosis ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Metalloendopeptidases - antagonists &amp; inhibitors ; Metalloendopeptidases - metabolism ; Mice ; Myocardium - metabolism ; Myocardium - pathology ; RNA Interference ; Signal Transduction ; Up-Regulation</subject><ispartof>Journal of molecular and cellular cardiology, 2015-03, Vol.80, p.101-109</ispartof><rights>2015</rights><rights>Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-d4cdafea4afe116e1bd0c52ced50ab40c0cadac0ae9b564f902ca19d5cac3b623</citedby><cites>FETCH-LOGICAL-c480t-d4cdafea4afe116e1bd0c52ced50ab40c0cadac0ae9b564f902ca19d5cac3b623</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.2015.01.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25584774$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Xianwei</creatorcontrib><creatorcontrib>Guo, Zhikun</creatorcontrib><creatorcontrib>Ding, Zufeng</creatorcontrib><creatorcontrib>Khaidakov, Magomed</creatorcontrib><creatorcontrib>Lin, Juntang</creatorcontrib><creatorcontrib>Xu, Zhenping</creatorcontrib><creatorcontrib>Sharma, Shree G</creatorcontrib><creatorcontrib>Jiwani, Shahanawaz</creatorcontrib><creatorcontrib>Mehta, Jawahar L</creatorcontrib><title>Endothelin-1 upregulation mediates aging-related cardiac fibrosis</title><title>Journal of molecular and cellular cardiology</title><addtitle>J Mol Cell Cardiol</addtitle><description>Abstract Endothelin-1 (ET-1) plays a major role in regulating myocardial fibrosis in several pathological conditions, such as hypertension and diabetes. 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ET-1 upregulation with aging was also seen in ≈ 70-year old (vs. ≈ 30-year old) human heart sections. In concert with ET-1 upregulation, the expression of fibronectin and collagens was found to be markedly increased in P30 cardiac fibroblasts in culture, fibroblasts isolated from the aged mice hearts, and in aged human hearts. Interestingly, inhibition of ET-1 in the senescent P30 fibroblasts by 2 different strategies (the use of siRNA and the use of endothelin converting enzyme inhibitors) markedly suppressed expression of fibrosis signals. Further, treatment with synthetic ET-1 enhanced fibronectin and collagen expression in P3 cardiac fibroblasts. 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inhibitors</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Mice</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Up-Regulation</subject><issn>0022-2828</issn><issn>1095-8584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFP3DAQha2qqGxpf0EllGMvCTOOHZIDlRCiFAmpB-BsOePJ1iGbbO0Eaf99vSz00EsvtjR6z-P3PSG-IBQIWJ31xa7fEBUSUBeABQC-EyuERue1rtV7sQKQMpe1rI_Fxxh7AGhUWX4Qx1Inwfm5WonL69FN8y8e_JhjtmwDr5fBzn4asw07b2eOmV37cZ0HTnN2GdmQ5pR1vg1T9PGTOOrsEPnz630iHr9fP1z9yO9-3txeXd7lpGqYc6fI2Y6tSgdixdg6IC2JnQbbKiAg6yyB5abVleoakGSxcZoslW0lyxPx9fDuNky_F46z2fhIPAx25GmJBqsKlNRNg0laHqSUfhgDd2Yb_MaGnUEwe3amNy_szJ6dATSJXXKdvi5Y2pT9r-cNVhJcHAScYj57DiaS5zFF8IFpNm7y_1nw7R8_Jeye7PDEO479tIQxETRoojRg7vf17dtDnZoDqco_ixeXMA</recordid><startdate>20150301</startdate><enddate>20150301</enddate><creator>Wang, Xianwei</creator><creator>Guo, Zhikun</creator><creator>Ding, Zufeng</creator><creator>Khaidakov, Magomed</creator><creator>Lin, Juntang</creator><creator>Xu, Zhenping</creator><creator>Sharma, Shree G</creator><creator>Jiwani, Shahanawaz</creator><creator>Mehta, Jawahar L</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>20150301</creationdate><title>Endothelin-1 upregulation mediates aging-related cardiac fibrosis</title><author>Wang, Xianwei ; 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Aging is an independent risk factor for myocardial fibrosis. We hypothesized that ET-1 upregulation may be a basis of enhanced collagen synthesis in the senescent fibroblasts resulting in cardiac fibrosis with aging. To examine this hypothesis, we cultured mouse cardiac fibroblasts to passage-30 (P30). β–Galactosidase activity and several other aging markers were markedly increased in P30 (vs. P3) fibroblasts, indicating that these cells were indeed undergoing senescence. Importantly, ET-1 expression was markedly upregulated in P30 (vs. P3) fibroblasts. Of note, estrogen receptor-α (ER-α), an important negative regulator of ET-1, was downregulated in P30 fibroblasts. We also studied aged (130-weeks old, female) mice hearts, and observed that ET-1 was upregulated and ER-α was downregulated in these hearts (vs. 6-week old mice hearts, female). Similar observations were made in the fibroblasts isolated from aged mice hearts. ET-1 upregulation with aging was also seen in ≈ 70-year old (vs. ≈ 30-year old) human heart sections. In concert with ET-1 upregulation, the expression of fibronectin and collagens was found to be markedly increased in P30 cardiac fibroblasts in culture, fibroblasts isolated from the aged mice hearts, and in aged human hearts. Interestingly, inhibition of ET-1 in the senescent P30 fibroblasts by 2 different strategies (the use of siRNA and the use of endothelin converting enzyme inhibitors) markedly suppressed expression of fibrosis signals. Further, treatment with synthetic ET-1 enhanced fibronectin and collagen expression in P3 cardiac fibroblasts. These observations in mice and human hearts suggest that aging-related cardiac fibrosis is, at least partially, dependent on the upregulation of ET-1.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25584774</pmid><doi>10.1016/j.yjmcc.2015.01.001</doi><tpages>9</tpages></addata></record>
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subjects Aging
Aging - genetics
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - metabolism
beta-Galactosidase - metabolism
Cardiac fibrosis
Cardiovascular
Cellular Senescence - genetics
Collagens
Endothelin-1
Endothelin-1 - genetics
Endothelin-1 - metabolism
Endothelin-Converting Enzymes
Enzyme Activation
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Female
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibronectin
Fibrosis
Gene Expression Regulation
Gene Knockdown Techniques
Humans
Metalloendopeptidases - antagonists & inhibitors
Metalloendopeptidases - metabolism
Mice
Myocardium - metabolism
Myocardium - pathology
RNA Interference
Signal Transduction
Up-Regulation
title Endothelin-1 upregulation mediates aging-related cardiac fibrosis
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