- Email: [email protected]
Mitochondria, contractile apparatus, and ion channels in the failing myocardium: Special relationships or dangerous liaisons?
Author's Accepted Manuscript
Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons? Matteo Vatta PhD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(16)00123-5 http://dx.doi.org/10.1016/j.hrthm.2016.01.023 HRTHM6603
To appear in:
Heart Rhythm
Cite this article as: Matteo Vatta PhD, Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons?, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.01.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons?
Matteo Vatta, PhD,1,2 From the 1Department of Medical and Molecular Genetics, Indiana University School of Medicine and 2Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, the Indianapolis, IN
Address for correspondence Matteo Vatta, PhD, FACMG 550 University Blvd, UH AOC 6029, Indianapolis, IN 46202 Phone 317 944-1066, Email: [email protected]
Acknowledgments This publication was made possible by the Indiana University Health— Indiana University School of Medicine Strategic Research Initiative.
1
Heart Failure remains a leading cause of morbidity and mortality in the US and around the world due to the high risk of progressive pump failure or sudden cardiac death. Despite important discoveries and improvements in patient care in the last few decades, we still lack a clear understanding about the molecular changes that occur during early development of the disease, which could explain its progression and the pro-arrhythmic substrate. Cardiac remodeling is a very well known biological process, which involves the reprogramming of gene expression to compensate for the reduced electro-mechanical performance. In this issue of the journal, Barth et al. reported meta-analysis of a large microarray dataset from normal and failing murine and human myocardium from the publicly available database Gene Expression Omnibus (GEO).1 The authors divided the investigated genes into Gene Ontology (GO) categories with genetic and functional similarities across species. They identified 55 ion channel and transporter genes co-expressed with genes coding for proteins involved in oxidative phosphorylation (OXPHOS), citric acid cycle, glycolysis, fatty acid metabolism, muscle contraction, sarcomere, and Z-disc, while other sets of ion channel genes were associated with the GO clusters of signal transduction and transcription/translation. 1 In particular, major myocardial ion channels genes such as SCN5A, KCNH2, GJA1, and ATP2B, previously associated with primary arrhythmias and heart failure, showed a positive correlation with the expression of genes involved in mitochondrial biology and electron transport chain. 1 The genetic correlation between cardiac ion channels and metabolic gene products was also partially supported by the available physical interaction data between some of the studied gene targets, albeit based on inhomogeneous experimental assays collected over many years employing various technical approaches such as two yeast hybrid system, affinity-captures mass spectrometry, protein overlay, and coimmuno precipitation, among the others. The basic metabolic processes occurring in normal and failing heart have been known for long time. The production and utilization of ATP is at the corner stone of cardiac energy
2
supply and expenditure and most ATP is generated during oxidative phosphorylation in the mitochondria, while approximately 5% derives from glycolysis and marginally from the citric acid cycle. 2 Therefore, any cause of sustained hindrance in ATP generation, could potentially initiate a biological and molecular cascade of events leading to contractile dysfunction.3 Previous studies employing different models of heart failure such as mouse with transverse aortic constriction (TAC) induced pressure overload hypertrophy,4 right ventricular remodeling in human Hypoplastic Left Heart Syndrome (HLHS), 5 or explanted hearts from nonischemic dilated cardiomyopathy patients, 6 demonstrated a maladaptive metabolic response with OXPHOS genes most significantly affected, suggesting a shift from the normal fatty acid metabolism to glucose metabolism in myocytes undergoing hypertrophy. 4,5,6 Thus, irrespective of the underlying etiology, cardiac remodeling represents a common process in which early mitochondrial dysfunction resulting in energy deprivation could lead to the metabolic shift, which originates the cascade of events ultimately leading to mechanical dysfunction. 7 Altered glucose metabolism could occur at early stages of myocardial remodeling, thus preceding mechanical changes during hypertrophy progression and before presentation of clinical symptoms. 4 In the TAC mice model, early treatment with propranolol or rapamycin (mTOR inhibition), known to influence glucose uptake and G6P levels respectively, was able to prevent the maladaptive metabolic response and preserve myocardial function. 4 Although the interaction between metabolic pathways and sarcomeric or cytoskeletal proteins have not been fully elucidated, it is worth mentioning that components of the contractile apparatus, such as the LDB3-coded Z-disk protein ZASP, have been previously shown to interact with and modulate phosphoglucomutase-1 function, a key glycolytic enzyme, which facilitates the forward and reverse conversion of glucose 1-phosphate (G1P) from or to glucose
3
6-phosphate (G6P), thus potentially linking the metabolic derangement to mechanosensor hindrance and contractile dysfunction. 8 In addition, cardiac metabolic derangement was shown to be accompanied also by the altered expression profile of ion channels including those involved in calcium mobilization. 5,6 The cardiac action potential duration undergoes progressive prolongation from the early stages of myocardial remodeling, resulting from an electrical imbalance providing a substrate for arrhythmias, which could precede the clinical presentation of heart failure as it occurs in some forms of human cardiomyopathies. 9,10 A possible metabolic mechanism affecting myocardial electrical homeostasis is the response of cardiomyocyte cell stress signaling activating cAMPdependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which have a dramatic effect on ion channels function and transcription.,11,12 Furthermore, the abnormal electric activity in the insulted myocardium could, at least in part, be determined by the intricate connection between the cardiomyocyte cytoskeleton and the ion channels governing the cardiac action potential, 13 as demonstrated by genetic variants in genes coding for adaptor or structural proteins in human sudden cardiac death syndromes, 10,14 explaining the higher susceptibility to malignant arrhythmias in the failing myocardium. In their report, Barth et al. were able to interrogate all major available databases to provide a comprehensive genome-wide expression profile and genetic interaction analysis, summarizing the wealth of information collected over the last decades, thus helping to frame the still eluding detailed picture of early heart failure development. An important limitation of the currently available databases is that most microarray data used for the meta-analysis have been collected using different technical platforms, resolution and coverage parameters. Similarly, even the most advanced expression arrays cannot 4
effectively distinguish between all possible alternatively spliced gene products or detect novel isoforms resulting from abnormal splicing mechanisms occurring during the disease process. The employment of current technologies such as massive parallel RNA sequencing for the whole transcriptome could provide more homogeneous and finely tuned details at high resolution for gene transcripts derived from an increasingly recognized genomic plasticity. Notwithstanding those limitations, the finding that the dramatic downregulation of metabolic transcripts in the failing myocardium was linked to an equally significant decline in the expression of the major myocardial ion channels, transporters and connexins, along with contractile proteins, prompts the intriguing speculation that contractile dysfunction and arrhythmogenesis may ultimately both result from the maladaptive metabolic remodeling in the failing myocardium. The clinical implications of such knowledge are significant, especially in those cases where heritable causes could be well established, such in familiar cardiomyopathies. In fact, if a molecular culprit is positively identified in a proband and in all at-risk first degree relatives, a presymptomatic treatment using approved medications, that have been shown to prevent the development of contractile dysfunction in animal models of heart failure, could be employed along with recommended clinical surveillance. Despite this optimistic and wishful perspective, further research is needed to determine the temporal and spatial molecular alterations occurring in the failing myocardium, before attempting any applications at the clinical side. The report from Barth et al., however, brings forth a comprehensive viewpoint, which will serve as framework for future investigations.
5
References 1. Barth AS, Kumordzie A; Tomaselli GF. Orchestrated Regulation of Energy Supply and Energy Expenditure: Transcriptional Co-Expression of Metabolism, Ion Homeostasis and Sarcomere Genes in Mammalian Myocardium. Heart Rhythm 2016 2. Gibbs CL. Cardiac energetics. Physiol Rev. 1978; 58:174–254. 3. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013 Aug 30; 113(6):709-24. PMID: 23989714 4. Kundu BK, Zhong M, Sen S, Davogustto G, Keller SR, Taegtmeyer H. Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Cardiology. 2015; 130(4):211-20. PMID: 25791172 5. Ricci M, Xu Y, Hammond HL, Willoughby DA, Nathanson L, Rodriguez MM, Vatta M, Lipshultz SE, Lincoln J. Myocardial alternative RNA splicing and gene expression profiling in early stage hypoplastic left heart syndrome. PLoS One. 2012;7(1):e29784. PMID: 22299024 6. Parajuli N, Valtuille L, Basu R, Famulski KS, Halloran PF, Sergi C, Oudit GY. Determinants of ventricular arrhythmias in human explanted hearts with dilated cardiomyopathy. Eur J Clin Invest. 2015 Oct 7. PMID: 26444674 7. Hamilton DJ, Zhang A, Li S, Cao TN, Smith JA, Vedula I, Cordero-Reyes AM, Youker KA, Torre-Amione G, Gupte AA. Combination of Angiotensin II and L-NG-Nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure. Am J Physiol Heart Circ Physiol. 2016 Jan 8:ajpheart.00746.2015. PMID: 26747502 8. Arimura T, Inagaki N, Hayashi T, Shichi D, Sato A, Hinohara K, Vatta M, Towbin JA, Chikamori T, Yamashina A, Kimura A: Impaired binding of ZASP/Cypher with 6
phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovasc Res 2009; 83:80–88. 9. Li Z, Ai T, Samani K, et al. A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. Circ Arrhythm Electrophysiol. 2010 Dec;3(6):646-56. PMID: 20852297 10. Vatta M, Spoonamore KG. Trends in Cardiovascular Medicine. Use of genetic testing to identify sudden cardiac death syndromes. 2015 Mar 12. pii: S1050-1738(15)00080-8 [PMID: 25864170] 11. Wagner S, Rokita AG, Anderson ME, Maier LS. Redox regulation of sodium and calcium handling. Antioxid Redox Signal. 2013 Mar 20;18(9):1063-77. PMID: 22900788 12. Ronkainen JJ, Hänninen SL, Korhonen T, Koivumäki JT, Skoumal R, Rautio S, Ronkainen VP, Tavi P. Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation. J Physiol. 2011 Jun 1;589(Pt 11):2669-86. PMID: 21486818 13. Vatta M, Faulkner G. Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle. Future Cardiology, 2006 Jul 2 (4), 467-476 [PMID: 19774097] 14. Vatta M, Ackerman MJ Ye B, Makielski J, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant Caveolin-3 Induces Persistent Late Sodium Current and is Associated with Long QT Syndrome. Circulation 2006 Nov 14;114(20):2104-12 [PMID: 17060380]
7
Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons? Matteo Vatta PhD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(16)00123-5 http://dx.doi.org/10.1016/j.hrthm.2016.01.023 HRTHM6603
To appear in:
Heart Rhythm
Cite this article as: Matteo Vatta PhD, Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons?, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.01.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mitochondria, contractile apparatus and ion channels in the failing myocardium: special relationships or dangerous liaisons?
Matteo Vatta, PhD,1,2 From the 1Department of Medical and Molecular Genetics, Indiana University School of Medicine and 2Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, the Indianapolis, IN
Address for correspondence Matteo Vatta, PhD, FACMG 550 University Blvd, UH AOC 6029, Indianapolis, IN 46202 Phone 317 944-1066, Email: [email protected]
Acknowledgments This publication was made possible by the Indiana University Health— Indiana University School of Medicine Strategic Research Initiative.
1
Heart Failure remains a leading cause of morbidity and mortality in the US and around the world due to the high risk of progressive pump failure or sudden cardiac death. Despite important discoveries and improvements in patient care in the last few decades, we still lack a clear understanding about the molecular changes that occur during early development of the disease, which could explain its progression and the pro-arrhythmic substrate. Cardiac remodeling is a very well known biological process, which involves the reprogramming of gene expression to compensate for the reduced electro-mechanical performance. In this issue of the journal, Barth et al. reported meta-analysis of a large microarray dataset from normal and failing murine and human myocardium from the publicly available database Gene Expression Omnibus (GEO).1 The authors divided the investigated genes into Gene Ontology (GO) categories with genetic and functional similarities across species. They identified 55 ion channel and transporter genes co-expressed with genes coding for proteins involved in oxidative phosphorylation (OXPHOS), citric acid cycle, glycolysis, fatty acid metabolism, muscle contraction, sarcomere, and Z-disc, while other sets of ion channel genes were associated with the GO clusters of signal transduction and transcription/translation. 1 In particular, major myocardial ion channels genes such as SCN5A, KCNH2, GJA1, and ATP2B, previously associated with primary arrhythmias and heart failure, showed a positive correlation with the expression of genes involved in mitochondrial biology and electron transport chain. 1 The genetic correlation between cardiac ion channels and metabolic gene products was also partially supported by the available physical interaction data between some of the studied gene targets, albeit based on inhomogeneous experimental assays collected over many years employing various technical approaches such as two yeast hybrid system, affinity-captures mass spectrometry, protein overlay, and coimmuno precipitation, among the others. The basic metabolic processes occurring in normal and failing heart have been known for long time. The production and utilization of ATP is at the corner stone of cardiac energy
2
supply and expenditure and most ATP is generated during oxidative phosphorylation in the mitochondria, while approximately 5% derives from glycolysis and marginally from the citric acid cycle. 2 Therefore, any cause of sustained hindrance in ATP generation, could potentially initiate a biological and molecular cascade of events leading to contractile dysfunction.3 Previous studies employing different models of heart failure such as mouse with transverse aortic constriction (TAC) induced pressure overload hypertrophy,4 right ventricular remodeling in human Hypoplastic Left Heart Syndrome (HLHS), 5 or explanted hearts from nonischemic dilated cardiomyopathy patients, 6 demonstrated a maladaptive metabolic response with OXPHOS genes most significantly affected, suggesting a shift from the normal fatty acid metabolism to glucose metabolism in myocytes undergoing hypertrophy. 4,5,6 Thus, irrespective of the underlying etiology, cardiac remodeling represents a common process in which early mitochondrial dysfunction resulting in energy deprivation could lead to the metabolic shift, which originates the cascade of events ultimately leading to mechanical dysfunction. 7 Altered glucose metabolism could occur at early stages of myocardial remodeling, thus preceding mechanical changes during hypertrophy progression and before presentation of clinical symptoms. 4 In the TAC mice model, early treatment with propranolol or rapamycin (mTOR inhibition), known to influence glucose uptake and G6P levels respectively, was able to prevent the maladaptive metabolic response and preserve myocardial function. 4 Although the interaction between metabolic pathways and sarcomeric or cytoskeletal proteins have not been fully elucidated, it is worth mentioning that components of the contractile apparatus, such as the LDB3-coded Z-disk protein ZASP, have been previously shown to interact with and modulate phosphoglucomutase-1 function, a key glycolytic enzyme, which facilitates the forward and reverse conversion of glucose 1-phosphate (G1P) from or to glucose
3
6-phosphate (G6P), thus potentially linking the metabolic derangement to mechanosensor hindrance and contractile dysfunction. 8 In addition, cardiac metabolic derangement was shown to be accompanied also by the altered expression profile of ion channels including those involved in calcium mobilization. 5,6 The cardiac action potential duration undergoes progressive prolongation from the early stages of myocardial remodeling, resulting from an electrical imbalance providing a substrate for arrhythmias, which could precede the clinical presentation of heart failure as it occurs in some forms of human cardiomyopathies. 9,10 A possible metabolic mechanism affecting myocardial electrical homeostasis is the response of cardiomyocyte cell stress signaling activating cAMPdependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which have a dramatic effect on ion channels function and transcription.,11,12 Furthermore, the abnormal electric activity in the insulted myocardium could, at least in part, be determined by the intricate connection between the cardiomyocyte cytoskeleton and the ion channels governing the cardiac action potential, 13 as demonstrated by genetic variants in genes coding for adaptor or structural proteins in human sudden cardiac death syndromes, 10,14 explaining the higher susceptibility to malignant arrhythmias in the failing myocardium. In their report, Barth et al. were able to interrogate all major available databases to provide a comprehensive genome-wide expression profile and genetic interaction analysis, summarizing the wealth of information collected over the last decades, thus helping to frame the still eluding detailed picture of early heart failure development. An important limitation of the currently available databases is that most microarray data used for the meta-analysis have been collected using different technical platforms, resolution and coverage parameters. Similarly, even the most advanced expression arrays cannot 4
effectively distinguish between all possible alternatively spliced gene products or detect novel isoforms resulting from abnormal splicing mechanisms occurring during the disease process. The employment of current technologies such as massive parallel RNA sequencing for the whole transcriptome could provide more homogeneous and finely tuned details at high resolution for gene transcripts derived from an increasingly recognized genomic plasticity. Notwithstanding those limitations, the finding that the dramatic downregulation of metabolic transcripts in the failing myocardium was linked to an equally significant decline in the expression of the major myocardial ion channels, transporters and connexins, along with contractile proteins, prompts the intriguing speculation that contractile dysfunction and arrhythmogenesis may ultimately both result from the maladaptive metabolic remodeling in the failing myocardium. The clinical implications of such knowledge are significant, especially in those cases where heritable causes could be well established, such in familiar cardiomyopathies. In fact, if a molecular culprit is positively identified in a proband and in all at-risk first degree relatives, a presymptomatic treatment using approved medications, that have been shown to prevent the development of contractile dysfunction in animal models of heart failure, could be employed along with recommended clinical surveillance. Despite this optimistic and wishful perspective, further research is needed to determine the temporal and spatial molecular alterations occurring in the failing myocardium, before attempting any applications at the clinical side. The report from Barth et al., however, brings forth a comprehensive viewpoint, which will serve as framework for future investigations.
5
References 1. Barth AS, Kumordzie A; Tomaselli GF. Orchestrated Regulation of Energy Supply and Energy Expenditure: Transcriptional Co-Expression of Metabolism, Ion Homeostasis and Sarcomere Genes in Mammalian Myocardium. Heart Rhythm 2016 2. Gibbs CL. Cardiac energetics. Physiol Rev. 1978; 58:174–254. 3. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013 Aug 30; 113(6):709-24. PMID: 23989714 4. Kundu BK, Zhong M, Sen S, Davogustto G, Keller SR, Taegtmeyer H. Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Cardiology. 2015; 130(4):211-20. PMID: 25791172 5. Ricci M, Xu Y, Hammond HL, Willoughby DA, Nathanson L, Rodriguez MM, Vatta M, Lipshultz SE, Lincoln J. Myocardial alternative RNA splicing and gene expression profiling in early stage hypoplastic left heart syndrome. PLoS One. 2012;7(1):e29784. PMID: 22299024 6. Parajuli N, Valtuille L, Basu R, Famulski KS, Halloran PF, Sergi C, Oudit GY. Determinants of ventricular arrhythmias in human explanted hearts with dilated cardiomyopathy. Eur J Clin Invest. 2015 Oct 7. PMID: 26444674 7. Hamilton DJ, Zhang A, Li S, Cao TN, Smith JA, Vedula I, Cordero-Reyes AM, Youker KA, Torre-Amione G, Gupte AA. Combination of Angiotensin II and L-NG-Nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure. Am J Physiol Heart Circ Physiol. 2016 Jan 8:ajpheart.00746.2015. PMID: 26747502 8. Arimura T, Inagaki N, Hayashi T, Shichi D, Sato A, Hinohara K, Vatta M, Towbin JA, Chikamori T, Yamashina A, Kimura A: Impaired binding of ZASP/Cypher with 6
phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovasc Res 2009; 83:80–88. 9. Li Z, Ai T, Samani K, et al. A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. Circ Arrhythm Electrophysiol. 2010 Dec;3(6):646-56. PMID: 20852297 10. Vatta M, Spoonamore KG. Trends in Cardiovascular Medicine. Use of genetic testing to identify sudden cardiac death syndromes. 2015 Mar 12. pii: S1050-1738(15)00080-8 [PMID: 25864170] 11. Wagner S, Rokita AG, Anderson ME, Maier LS. Redox regulation of sodium and calcium handling. Antioxid Redox Signal. 2013 Mar 20;18(9):1063-77. PMID: 22900788 12. Ronkainen JJ, Hänninen SL, Korhonen T, Koivumäki JT, Skoumal R, Rautio S, Ronkainen VP, Tavi P. Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation. J Physiol. 2011 Jun 1;589(Pt 11):2669-86. PMID: 21486818 13. Vatta M, Faulkner G. Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle. Future Cardiology, 2006 Jul 2 (4), 467-476 [PMID: 19774097] 14. Vatta M, Ackerman MJ Ye B, Makielski J, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant Caveolin-3 Induces Persistent Late Sodium Current and is Associated with Long QT Syndrome. Circulation 2006 Nov 14;114(20):2104-12 [PMID: 17060380]
7