Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade
We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombi...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Masao Kakoki [verfasserIn] |
|---|
| Format: |
Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
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| Schlagwörter: |
Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism |
|---|
| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 16, Seite 5141-5146 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:16 ; pages:5141-5146 |
| Links: |
|---|
| DOI / URN: |
10.1073/pnas.1504557112 |
|---|
| Katalog-ID: |
OLC197026666X |
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| 520 | |a We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. | ||
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| 650 | 4 | |a Endothelin-1 - metabolism | |
| 650 | 4 | |a Myocardium - metabolism | |
| 650 | 4 | |a Aging - pathology | |
| 650 | 4 | |a Superoxides - metabolism | |
| 650 | 4 | |a Myocardium - pathology | |
| 650 | 4 | |a Superoxide Dismutase - metabolism | |
| 650 | 4 | |a Cardiomyopathy, Dilated - metabolism | |
| 650 | 4 | |a Matrix Metalloproteinase 9 - metabolism | |
| 650 | 4 | |a Collagen - metabolism | |
| 650 | 4 | |a Cardiomyopathy, Dilated - pathology | |
| 650 | 4 | |a Myocardium - enzymology | |
| 650 | 4 | |a Gene expression | |
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| 700 | 0 | |a Catherine K. Hathaway |4 oth | |
| 700 | 0 | |a Ruriko Grant |4 oth | |
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| 700 | 0 | |a Albert S. Chang |4 oth | |
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| 700 | 0 | |a Sylvia Hiller |4 oth | |
| 700 | 0 | |a Oliver Smithies |4 oth | |
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| 700 | 0 | |a Bingruo Wu |4 oth | |
| 700 | 0 | |a Bin Zhou |4 oth | |
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10.1073/pnas.1504557112 doi PQ20160211 (DE-627)OLC197026666X (DE-599)GBVOLC197026666X (PRQ)c2217-d82392dbc6f53ce03cd8db472d7970c7e63ea5b7e25b2d6e721fb28d73a368073 (KEY)0583363920150000112001605141endothelin1criticallyinfluencescardiacfunctionvias DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Masao Kakoki verfasserin aut Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Endothelin-1 - metabolism Myocardium - metabolism Aging - pathology Superoxides - metabolism Myocardium - pathology Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism Collagen - metabolism Cardiomyopathy, Dilated - pathology Myocardium - enzymology Gene expression Proteins Cardiovascular system Organic chemicals Rodents Victoria J. Madden oth Hyung-Suk Kim oth Longquan Xu oth John R. Hagaman oth Catherine K. Hathaway oth Ruriko Grant oth Feng Li oth Albert S. Chang oth Mauricio Rojas oth Sylvia Hiller oth Oliver Smithies oth C. Robert Bagnell oth Bingruo Wu oth Bin Zhou oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 16, Seite 5141-5146 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:16 pages:5141-5146 http://dx.doi.org/10.1073/pnas.1504557112 Volltext http://www.pnas.org/content/112/16/5141.abstract http://www.ncbi.nlm.nih.gov/pubmed/25848038 http://search.proquest.com/docview/1678102677 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 16 5141-5146 |
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10.1073/pnas.1504557112 doi PQ20160211 (DE-627)OLC197026666X (DE-599)GBVOLC197026666X (PRQ)c2217-d82392dbc6f53ce03cd8db472d7970c7e63ea5b7e25b2d6e721fb28d73a368073 (KEY)0583363920150000112001605141endothelin1criticallyinfluencescardiacfunctionvias DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Masao Kakoki verfasserin aut Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Endothelin-1 - metabolism Myocardium - metabolism Aging - pathology Superoxides - metabolism Myocardium - pathology Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism Collagen - metabolism Cardiomyopathy, Dilated - pathology Myocardium - enzymology Gene expression Proteins Cardiovascular system Organic chemicals Rodents Victoria J. Madden oth Hyung-Suk Kim oth Longquan Xu oth John R. Hagaman oth Catherine K. Hathaway oth Ruriko Grant oth Feng Li oth Albert S. Chang oth Mauricio Rojas oth Sylvia Hiller oth Oliver Smithies oth C. Robert Bagnell oth Bingruo Wu oth Bin Zhou oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 16, Seite 5141-5146 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:16 pages:5141-5146 http://dx.doi.org/10.1073/pnas.1504557112 Volltext http://www.pnas.org/content/112/16/5141.abstract http://www.ncbi.nlm.nih.gov/pubmed/25848038 http://search.proquest.com/docview/1678102677 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 16 5141-5146 |
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10.1073/pnas.1504557112 doi PQ20160211 (DE-627)OLC197026666X (DE-599)GBVOLC197026666X (PRQ)c2217-d82392dbc6f53ce03cd8db472d7970c7e63ea5b7e25b2d6e721fb28d73a368073 (KEY)0583363920150000112001605141endothelin1criticallyinfluencescardiacfunctionvias DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Masao Kakoki verfasserin aut Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Endothelin-1 - metabolism Myocardium - metabolism Aging - pathology Superoxides - metabolism Myocardium - pathology Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism Collagen - metabolism Cardiomyopathy, Dilated - pathology Myocardium - enzymology Gene expression Proteins Cardiovascular system Organic chemicals Rodents Victoria J. Madden oth Hyung-Suk Kim oth Longquan Xu oth John R. Hagaman oth Catherine K. Hathaway oth Ruriko Grant oth Feng Li oth Albert S. Chang oth Mauricio Rojas oth Sylvia Hiller oth Oliver Smithies oth C. Robert Bagnell oth Bingruo Wu oth Bin Zhou oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 16, Seite 5141-5146 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:16 pages:5141-5146 http://dx.doi.org/10.1073/pnas.1504557112 Volltext http://www.pnas.org/content/112/16/5141.abstract http://www.ncbi.nlm.nih.gov/pubmed/25848038 http://search.proquest.com/docview/1678102677 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 16 5141-5146 |
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10.1073/pnas.1504557112 doi PQ20160211 (DE-627)OLC197026666X (DE-599)GBVOLC197026666X (PRQ)c2217-d82392dbc6f53ce03cd8db472d7970c7e63ea5b7e25b2d6e721fb28d73a368073 (KEY)0583363920150000112001605141endothelin1criticallyinfluencescardiacfunctionvias DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Masao Kakoki verfasserin aut Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Endothelin-1 - metabolism Myocardium - metabolism Aging - pathology Superoxides - metabolism Myocardium - pathology Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism Collagen - metabolism Cardiomyopathy, Dilated - pathology Myocardium - enzymology Gene expression Proteins Cardiovascular system Organic chemicals Rodents Victoria J. Madden oth Hyung-Suk Kim oth Longquan Xu oth John R. Hagaman oth Catherine K. Hathaway oth Ruriko Grant oth Feng Li oth Albert S. Chang oth Mauricio Rojas oth Sylvia Hiller oth Oliver Smithies oth C. Robert Bagnell oth Bingruo Wu oth Bin Zhou oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 16, Seite 5141-5146 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:16 pages:5141-5146 http://dx.doi.org/10.1073/pnas.1504557112 Volltext http://www.pnas.org/content/112/16/5141.abstract http://www.ncbi.nlm.nih.gov/pubmed/25848038 http://search.proquest.com/docview/1678102677 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 16 5141-5146 |
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10.1073/pnas.1504557112 doi PQ20160211 (DE-627)OLC197026666X (DE-599)GBVOLC197026666X (PRQ)c2217-d82392dbc6f53ce03cd8db472d7970c7e63ea5b7e25b2d6e721fb28d73a368073 (KEY)0583363920150000112001605141endothelin1criticallyinfluencescardiacfunctionvias DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Masao Kakoki verfasserin aut Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Endothelin-1 - metabolism Myocardium - metabolism Aging - pathology Superoxides - metabolism Myocardium - pathology Superoxide Dismutase - metabolism Cardiomyopathy, Dilated - metabolism Matrix Metalloproteinase 9 - metabolism Collagen - metabolism Cardiomyopathy, Dilated - pathology Myocardium - enzymology Gene expression Proteins Cardiovascular system Organic chemicals Rodents Victoria J. Madden oth Hyung-Suk Kim oth Longquan Xu oth John R. Hagaman oth Catherine K. Hathaway oth Ruriko Grant oth Feng Li oth Albert S. Chang oth Mauricio Rojas oth Sylvia Hiller oth Oliver Smithies oth C. Robert Bagnell oth Bingruo Wu oth Bin Zhou oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 16, Seite 5141-5146 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:16 pages:5141-5146 http://dx.doi.org/10.1073/pnas.1504557112 Volltext http://www.pnas.org/content/112/16/5141.abstract http://www.ncbi.nlm.nih.gov/pubmed/25848038 http://search.proquest.com/docview/1678102677 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 16 5141-5146 |
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Masao Kakoki @@aut@@ Victoria J. Madden @@oth@@ Hyung-Suk Kim @@oth@@ Longquan Xu @@oth@@ John R. Hagaman @@oth@@ Catherine K. Hathaway @@oth@@ Ruriko Grant @@oth@@ Feng Li @@oth@@ Albert S. Chang @@oth@@ Mauricio Rojas @@oth@@ Sylvia Hiller @@oth@@ Oliver Smithies @@oth@@ C. Robert Bagnell @@oth@@ Bingruo Wu @@oth@@ Bin Zhou @@oth@@ |
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endothelin-1 critically influences cardiac function via superoxide-mmp9 cascade |
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Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade |
| abstract |
We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. |
| abstractGer |
We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. |
| abstract_unstemmed |
We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction. |
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Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade |
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The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.</subfield></datafield><datafield tag="540" ind1=" " ind2=" "><subfield code="a">Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Endothelin-1 - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Myocardium - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Aging - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Superoxides - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Myocardium - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Superoxide Dismutase - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cardiomyopathy, Dilated - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Matrix Metalloproteinase 9 - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Collagen - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cardiomyopathy, Dilated - pathology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Myocardium - enzymology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene expression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cardiovascular system</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Organic chemicals</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Rodents</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Victoria J. 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