cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart
Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsi...
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Veröffentlicht in: | The Journal of biological chemistry 2015-12, Vol.290 (49), p.29250-29258 |
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description | Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function. |
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Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M115.681767</identifier><identifier>PMID: 26468277</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>8-Bromo Cyclic Adenosine Monophosphate - metabolism ; Animals ; cardiac metabolism ; cardiomyocyte ; Catalytic Domain ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - metabolism ; Cyclic AMP-Dependent Protein Kinase Type II - metabolism ; Cytoplasm - metabolism ; diabetes ; Diabetes Mellitus, Experimental - metabolism ; Disease Models, Animal ; heart ; Heart Failure - physiopathology ; Heart Ventricles - pathology ; Hemodynamics ; Lactates - metabolism ; Lipids - chemistry ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Bases of Disease ; Myocardial Contraction ; Myocardium - enzymology ; Myocytes, Cardiac - metabolism ; Phosphofructokinase-2 - metabolism ; Phosphorylation ; protein kinase A (PKA) ; Signal Transduction</subject><ispartof>The Journal of biological chemistry, 2015-12, Vol.290 (49), p.29250-29258</ispartof><rights>2015 © 2015 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2015 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2015 by The American Society for Biochemistry and Molecular Biology, Inc. 2015 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-5794f2e4c98507fc28bd926a5a0bed8fb2029ff31a8506f5402fda5b29fa6fed3</citedby><cites>FETCH-LOGICAL-c489t-5794f2e4c98507fc28bd926a5a0bed8fb2029ff31a8506f5402fda5b29fa6fed3</cites><orcidid>0000-0002-6167-3175</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705931/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705931/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26468277$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bockus, Lee B.</creatorcontrib><creatorcontrib>Humphries, Kenneth M.</creatorcontrib><title>cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.</description><subject>8-Bromo Cyclic Adenosine Monophosphate - metabolism</subject><subject>Animals</subject><subject>cardiac metabolism</subject><subject>cardiomyocyte</subject><subject>Catalytic Domain</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinase Type II - metabolism</subject><subject>Cytoplasm - metabolism</subject><subject>diabetes</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Disease Models, Animal</subject><subject>heart</subject><subject>Heart Failure - physiopathology</subject><subject>Heart Ventricles - pathology</subject><subject>Hemodynamics</subject><subject>Lactates - metabolism</subject><subject>Lipids - chemistry</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Bases of Disease</subject><subject>Myocardial Contraction</subject><subject>Myocardium - enzymology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Phosphofructokinase-2 - metabolism</subject><subject>Phosphorylation</subject><subject>protein kinase A (PKA)</subject><subject>Signal Transduction</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUFPGzEQha0KVFLKubfKRzhssL32en1BiiiFCBCR2krcLK89DkYbb2pvkPrv6yiA4IAvI3m-eTN6D6FvlEwpkfz0sbPTW0rFtGmpbOQnNKGkrata0Ps9NCGE0Uox0R6gLzk_kvK4op_RAWt40zIpJ-jOzm4XlYM1RAdxxIs0jBAivg7RZMDHi-vZCf4VltH0IS7xPOP5am1CAocLNT4A_hFMB2Ow-ApMGr-ifW_6DEfP9RD9-Xnx-_yqurm7nJ_PbirLWzVWQiruGXCrWkGkt6ztnGKNEYZ04FrfMcKU9zU1pd94wQnzzoiufJrGg6sP0dlOd73pVuBsuT2ZXq9TWJn0Tw8m6PedGB70cnjSXBKhaloEjp8F0vB3A3nUq5At9L2JMGyyppLzRmy3F_R0h9o05JzAv66hRG9j0CUGvY1B72IoE9_fXvfKv_heALUDoHj0FCDpbANEC65Ya0fthvCh-H-wRJbm</recordid><startdate>20151204</startdate><enddate>20151204</enddate><creator>Bockus, Lee B.</creator><creator>Humphries, Kenneth M.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6167-3175</orcidid></search><sort><creationdate>20151204</creationdate><title>cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart</title><author>Bockus, Lee B. ; Humphries, Kenneth M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-5794f2e4c98507fc28bd926a5a0bed8fb2029ff31a8506f5402fda5b29fa6fed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>8-Bromo Cyclic Adenosine Monophosphate - metabolism</topic><topic>Animals</topic><topic>cardiac metabolism</topic><topic>cardiomyocyte</topic><topic>Catalytic Domain</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinase Type II - metabolism</topic><topic>Cytoplasm - metabolism</topic><topic>diabetes</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Disease Models, Animal</topic><topic>heart</topic><topic>Heart Failure - physiopathology</topic><topic>Heart Ventricles - pathology</topic><topic>Hemodynamics</topic><topic>Lactates - metabolism</topic><topic>Lipids - chemistry</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Bases of Disease</topic><topic>Myocardial Contraction</topic><topic>Myocardium - enzymology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Phosphofructokinase-2 - metabolism</topic><topic>Phosphorylation</topic><topic>protein kinase A (PKA)</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bockus, Lee B.</creatorcontrib><creatorcontrib>Humphries, Kenneth M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bockus, Lee B.</au><au>Humphries, Kenneth M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2015-12-04</date><risdate>2015</risdate><volume>290</volume><issue>49</issue><spage>29250</spage><epage>29258</epage><pages>29250-29258</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26468277</pmid><doi>10.1074/jbc.M115.681767</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-6167-3175</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 8-Bromo Cyclic Adenosine Monophosphate - metabolism Animals cardiac metabolism cardiomyocyte Catalytic Domain Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - metabolism Cyclic AMP-Dependent Protein Kinase Type II - metabolism Cytoplasm - metabolism diabetes Diabetes Mellitus, Experimental - metabolism Disease Models, Animal heart Heart Failure - physiopathology Heart Ventricles - pathology Hemodynamics Lactates - metabolism Lipids - chemistry Male Mice Mice, Inbred C57BL Molecular Bases of Disease Myocardial Contraction Myocardium - enzymology Myocytes, Cardiac - metabolism Phosphofructokinase-2 - metabolism Phosphorylation protein kinase A (PKA) Signal Transduction |
title | cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart |
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