Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy
Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2010-09, Vol.122 (10), p.1004-1016 |
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| creator | MOSLEHI, Javid MINAMISHIMA, Yoji Andrew JIANRU SHI NEUBERG, Donna CHARYTAN, David M PADERA, Robert F SIGNORETTI, Sabina LIAO, Ronglih KAELIN, William G |
| description | Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment.
We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.
Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease. |
| doi_str_mv | 10.1161/circulationaha.109.922427 |
| format | Article |
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We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.
Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/circulationaha.109.922427</identifier><identifier>PMID: 20733101</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Animals ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiomyopathy, Dilated - metabolism ; Cardiomyopathy, Dilated - physiopathology ; Cell Hypoxia - physiology ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Fundamental and applied biological sciences. Psychology ; General aspects ; Heart Failure - metabolism ; Heart Failure - physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mitochondria - metabolism ; Myocardial Stunning - metabolism ; Myocardial Stunning - physiopathology ; Myocardium - metabolism ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - enzymology ; Neovascularization, Physiologic - physiology ; Phenotype ; Procollagen-Proline Dioxygenase - genetics ; Procollagen-Proline Dioxygenase - metabolism ; Vertebrates: cardiovascular system</subject><ispartof>Circulation (New York, N.Y.), 2010-09, Vol.122 (10), p.1004-1016</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c519t-8c86e3d9474a3fdabd0f25b3f6ae6420eeb2e46c8e353c0becb282083308e5193</citedby><cites>FETCH-LOGICAL-c519t-8c86e3d9474a3fdabd0f25b3f6ae6420eeb2e46c8e353c0becb282083308e5193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23214130$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20733101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MOSLEHI, Javid</creatorcontrib><creatorcontrib>MINAMISHIMA, Yoji Andrew</creatorcontrib><creatorcontrib>JIANRU SHI</creatorcontrib><creatorcontrib>NEUBERG, Donna</creatorcontrib><creatorcontrib>CHARYTAN, David M</creatorcontrib><creatorcontrib>PADERA, Robert F</creatorcontrib><creatorcontrib>SIGNORETTI, Sabina</creatorcontrib><creatorcontrib>LIAO, Ronglih</creatorcontrib><creatorcontrib>KAELIN, William G</creatorcontrib><title>Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment.
We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.
Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.</description><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cardiomyopathy, Dilated - metabolism</subject><subject>Cardiomyopathy, Dilated - physiopathology</subject><subject>Cell Hypoxia - physiology</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>General aspects</subject><subject>Heart Failure - metabolism</subject><subject>Heart Failure - physiopathology</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Mutant Strains</subject><subject>Mitochondria - metabolism</subject><subject>Myocardial Stunning - metabolism</subject><subject>Myocardial Stunning - physiopathology</subject><subject>Myocardium - metabolism</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Neovascularization, Physiologic - physiology</subject><subject>Phenotype</subject><subject>Procollagen-Proline Dioxygenase - genetics</subject><subject>Procollagen-Proline Dioxygenase - metabolism</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtr3DAUhUVpaSZp_0JxF6UrT_Tya2lMkzEMmaEkayNfXzMqsuVKdoj_fVVmkqzu6zvnwiHkO6NbxlJ2C9rBYtSs7ahOastosS04lzz7QDYs4TKWiSg-kg2ltIgzwfkVufb-TxhTkSWfyRWnmRCMsg1xe-t9ZPtot072Rau4HrsFdGswulMwWxcdnTWrCffO2ZfVKI9RCbN-1vMa6TGqlOu0HVYL64w-Op5wtGAnHfrawwkHDe_MpObT-oV86pXx-PVSb8jT3a_HahfvD_d1Ve5jSFgxxznkKYqukJlUou9U29GeJ63oU4Wp5BSx5ShTyFEkAmiL0PKc01wImmNwEDfk59l3cvbvgn5uBu0BjVEj2sU3WSIpF0nOAlmcSXAhDYd9Mzk9KLc2jDb_E2-q-nf1tC8f68NDuSvDumjOiQftt8uXpR2we1O-RhyAHxdAeVCmd2oE7d85wZlkgop_lZGPMQ</recordid><startdate>20100907</startdate><enddate>20100907</enddate><creator>MOSLEHI, Javid</creator><creator>MINAMISHIMA, Yoji Andrew</creator><creator>JIANRU SHI</creator><creator>NEUBERG, Donna</creator><creator>CHARYTAN, David M</creator><creator>PADERA, Robert F</creator><creator>SIGNORETTI, Sabina</creator><creator>LIAO, Ronglih</creator><creator>KAELIN, William G</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>20100907</creationdate><title>Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy</title><author>MOSLEHI, Javid ; MINAMISHIMA, Yoji Andrew ; JIANRU SHI ; NEUBERG, Donna ; CHARYTAN, David M ; PADERA, Robert F ; SIGNORETTI, Sabina ; LIAO, Ronglih ; KAELIN, William G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c519t-8c86e3d9474a3fdabd0f25b3f6ae6420eeb2e46c8e353c0becb282083308e5193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. 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Psychology</topic><topic>General aspects</topic><topic>Heart Failure - metabolism</topic><topic>Heart Failure - physiopathology</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Mutant Strains</topic><topic>Mitochondria - metabolism</topic><topic>Myocardial Stunning - metabolism</topic><topic>Myocardial Stunning - physiopathology</topic><topic>Myocardium - metabolism</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Neovascularization, Physiologic - physiology</topic><topic>Phenotype</topic><topic>Procollagen-Proline Dioxygenase - genetics</topic><topic>Procollagen-Proline Dioxygenase - metabolism</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MOSLEHI, Javid</creatorcontrib><creatorcontrib>MINAMISHIMA, Yoji Andrew</creatorcontrib><creatorcontrib>JIANRU SHI</creatorcontrib><creatorcontrib>NEUBERG, Donna</creatorcontrib><creatorcontrib>CHARYTAN, David M</creatorcontrib><creatorcontrib>PADERA, Robert F</creatorcontrib><creatorcontrib>SIGNORETTI, Sabina</creatorcontrib><creatorcontrib>LIAO, Ronglih</creatorcontrib><creatorcontrib>KAELIN, William G</creatorcontrib><collection>Pascal-Francis</collection><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>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MOSLEHI, Javid</au><au>MINAMISHIMA, Yoji Andrew</au><au>JIANRU SHI</au><au>NEUBERG, Donna</au><au>CHARYTAN, David M</au><au>PADERA, Robert F</au><au>SIGNORETTI, Sabina</au><au>LIAO, Ronglih</au><au>KAELIN, William G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2010-09-07</date><risdate>2010</risdate><volume>122</volume><issue>10</issue><spage>1004</spage><epage>1016</epage><pages>1004-1016</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment.
We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.
Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>20733101</pmid><doi>10.1161/circulationaha.109.922427</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation (New York, N.Y.), 2010-09, Vol.122 (10), p.1004-1016 |
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| subjects | Animals Basic Helix-Loop-Helix Transcription Factors - metabolism Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiomyopathy, Dilated - metabolism Cardiomyopathy, Dilated - physiopathology Cell Hypoxia - physiology Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Fundamental and applied biological sciences. Psychology General aspects Heart Failure - metabolism Heart Failure - physiopathology Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-Inducible Factor-Proline Dioxygenases Medical sciences Mice Mice, Inbred C57BL Mice, Mutant Strains Mitochondria - metabolism Myocardial Stunning - metabolism Myocardial Stunning - physiopathology Myocardium - metabolism Myocytes, Cardiac - cytology Myocytes, Cardiac - enzymology Neovascularization, Physiologic - physiology Phenotype Procollagen-Proline Dioxygenase - genetics Procollagen-Proline Dioxygenase - metabolism Vertebrates: cardiovascular system |
| title | Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy |
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