Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance
ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, trans...
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| Veröffentlicht in: | The EMBO journal 2003-04, Vol.22 (8), p.1732-1742 |
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| creator | Hodgson, Denice M Zingman, Leonid V Kane, Garvan C Perez-Terzic, Carmen Bienengraeber, Martin Ozcan, Cevher Gumina, Richard J Pucar, Darko O'Coclain, Fergus Mann, Douglas L Alekseev, Alexey E Terzic, Andre |
| description | ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy. |
| doi_str_mv | 10.1093/emboj/cdg192 |
| format | Article |
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However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.</description><identifier>ISSN: 0261-4189</identifier><identifier>DOI: 10.1093/emboj/cdg192</identifier><identifier>PMID: 12682006</identifier><language>eng</language><publisher>England</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Calcium - metabolism ; Cardiac Output, Low - metabolism ; Cardiotonic Agents - pharmacology ; Creatine Kinase - metabolism ; Dinitrophenols - pharmacology ; Female ; Ion Channel Gating ; Isoproterenol - pharmacology ; Male ; Mice ; Mitochondria - metabolism ; Myocardium - ultrastructure ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Patch-Clamp Techniques ; Potassium Channels - metabolism ; Transforming Growth Factor alpha - genetics ; Transforming Growth Factor alpha - metabolism ; Transgenes ; Uncoupling Agents - pharmacology ; Ventricular Remodeling - physiology</subject><ispartof>The EMBO journal, 2003-04, Vol.22 (8), p.1732-1742</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12682006$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hodgson, Denice M</creatorcontrib><creatorcontrib>Zingman, Leonid V</creatorcontrib><creatorcontrib>Kane, Garvan C</creatorcontrib><creatorcontrib>Perez-Terzic, Carmen</creatorcontrib><creatorcontrib>Bienengraeber, Martin</creatorcontrib><creatorcontrib>Ozcan, Cevher</creatorcontrib><creatorcontrib>Gumina, Richard J</creatorcontrib><creatorcontrib>Pucar, Darko</creatorcontrib><creatorcontrib>O'Coclain, Fergus</creatorcontrib><creatorcontrib>Mann, Douglas L</creatorcontrib><creatorcontrib>Alekseev, Alexey E</creatorcontrib><creatorcontrib>Terzic, Andre</creatorcontrib><title>Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><description>ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>Cardiac Output, Low - metabolism</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Creatine Kinase - metabolism</subject><subject>Dinitrophenols - pharmacology</subject><subject>Female</subject><subject>Ion Channel Gating</subject><subject>Isoproterenol - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mitochondria - metabolism</subject><subject>Myocardium - ultrastructure</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Potassium Channels - metabolism</subject><subject>Transforming Growth Factor alpha - genetics</subject><subject>Transforming Growth Factor alpha - metabolism</subject><subject>Transgenes</subject><subject>Uncoupling Agents - pharmacology</subject><subject>Ventricular Remodeling - physiology</subject><issn>0261-4189</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kD1PwzAURT2AaClszMgTgiH02U5ce6yq8iEqwVDEGDn2S5vKcYKdDPx7KlGmsxwd6V5Cbhg8MtBijm3VHebW7ZjmZ2QKXLIsZ0pPyGVKBwAo1IJdkAnjUnEAOSVfK_R-9CbSiG3n0DdhR5tA92jiQGvT-DEidU2KYz8k-na_3H48ULs3IaDPHPYYHIaBpiFiSnToPEYTLF6R89r4hNcnzsjn03q7esk278-vq-Um65nQQ1blzEIB1irNbC61MdLUReWUXijFpBW8Krh2GgRzUkpV51w6sEzkNRQWhJiRu79uH7vvEdNQtk2yx00mYDemciGYBFXwo3h7EseqRVf2sWlN_Cn_rxC_Mi9ezQ</recordid><startdate>20030415</startdate><enddate>20030415</enddate><creator>Hodgson, Denice M</creator><creator>Zingman, Leonid V</creator><creator>Kane, Garvan C</creator><creator>Perez-Terzic, Carmen</creator><creator>Bienengraeber, Martin</creator><creator>Ozcan, Cevher</creator><creator>Gumina, Richard J</creator><creator>Pucar, Darko</creator><creator>O'Coclain, Fergus</creator><creator>Mann, Douglas L</creator><creator>Alekseev, Alexey E</creator><creator>Terzic, Andre</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20030415</creationdate><title>Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance</title><author>Hodgson, Denice M ; Zingman, Leonid V ; Kane, Garvan C ; Perez-Terzic, Carmen ; Bienengraeber, Martin ; Ozcan, Cevher ; Gumina, Richard J ; Pucar, Darko ; O'Coclain, Fergus ; Mann, Douglas L ; Alekseev, Alexey E ; Terzic, Andre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p139t-b41c050cc891c469aa6af5bd8978816c32b529d9031d6668f426d0c134f05c033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>Cardiac Output, Low - metabolism</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Creatine Kinase - metabolism</topic><topic>Dinitrophenols - pharmacology</topic><topic>Female</topic><topic>Ion Channel Gating</topic><topic>Isoproterenol - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mitochondria - metabolism</topic><topic>Myocardium - ultrastructure</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Patch-Clamp Techniques</topic><topic>Potassium Channels - metabolism</topic><topic>Transforming Growth Factor alpha - genetics</topic><topic>Transforming Growth Factor alpha - metabolism</topic><topic>Transgenes</topic><topic>Uncoupling Agents - pharmacology</topic><topic>Ventricular Remodeling - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hodgson, Denice M</creatorcontrib><creatorcontrib>Zingman, Leonid V</creatorcontrib><creatorcontrib>Kane, Garvan C</creatorcontrib><creatorcontrib>Perez-Terzic, Carmen</creatorcontrib><creatorcontrib>Bienengraeber, Martin</creatorcontrib><creatorcontrib>Ozcan, Cevher</creatorcontrib><creatorcontrib>Gumina, Richard J</creatorcontrib><creatorcontrib>Pucar, Darko</creatorcontrib><creatorcontrib>O'Coclain, Fergus</creatorcontrib><creatorcontrib>Mann, Douglas L</creatorcontrib><creatorcontrib>Alekseev, Alexey E</creatorcontrib><creatorcontrib>Terzic, Andre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hodgson, Denice M</au><au>Zingman, Leonid V</au><au>Kane, Garvan C</au><au>Perez-Terzic, Carmen</au><au>Bienengraeber, Martin</au><au>Ozcan, Cevher</au><au>Gumina, Richard J</au><au>Pucar, Darko</au><au>O'Coclain, Fergus</au><au>Mann, Douglas L</au><au>Alekseev, Alexey E</au><au>Terzic, Andre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance</atitle><jtitle>The EMBO journal</jtitle><addtitle>EMBO J</addtitle><date>2003-04-15</date><risdate>2003</risdate><volume>22</volume><issue>8</issue><spage>1732</spage><epage>1742</epage><pages>1732-1742</pages><issn>0261-4189</issn><abstract>ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. 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| subjects | Adenosine Triphosphate - metabolism Animals Calcium - metabolism Cardiac Output, Low - metabolism Cardiotonic Agents - pharmacology Creatine Kinase - metabolism Dinitrophenols - pharmacology Female Ion Channel Gating Isoproterenol - pharmacology Male Mice Mitochondria - metabolism Myocardium - ultrastructure Myocytes, Cardiac - cytology Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Patch-Clamp Techniques Potassium Channels - metabolism Transforming Growth Factor alpha - genetics Transforming Growth Factor alpha - metabolism Transgenes Uncoupling Agents - pharmacology Ventricular Remodeling - physiology |
| title | Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance |
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