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Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation

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Abstract

Although ceramide accumulation in the heart is considered a major factor in promoting apoptosis and cardiac disorders, including heart failure, lipotoxicity and ischemia–reperfusion injury, little is known about ceramide’s role in mediating changes in contractility. In the present study, we measured the functional consequences of acute exposure of isolated field-stimulated adult rat cardiomyocytes to C6-ceramide. Exogenous ceramide treatment depressed the peak amplitude and the maximal velocity of shortening without altering intracellular calcium levels or kinetics. The inactive ceramide analog C6-dihydroceramide had no effect on myocyte shortening or [Ca2+]i transients. Experiments testing a potential role for C6-ceramide-mediated effects on activation of protein kinase C (PKC) demonstrated evidence for signaling through the calcium-independent isoform, PKCε. We employed 2-dimensional electrophoresis and anti-phospho-peptide antibodies to test whether treatment of the cardiomyocytes with C6-ceramide altered myocyte shortening via PKC-dependent phosphorylation of myofilament proteins. Compared to controls, myocytes treated with ceramide exhibited increased phosphorylation of myosin binding protein-C (cMyBP-C), specifically at Ser273 and Ser302, and troponin I (cTnI) at sites apart from Ser23/24, which could be attenuated with PKC inhibition. We conclude that the altered myofilament response to calcium resulting from multiple sites of PKC-dependent phosphorylation contributes to contractile dysfunction that is associated with cardiac diseases in which elevations in ceramides are present.

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References

  1. Ayaz-Guner S, Zhang J, Li L, Walker JW, Ge Y (2009) In vivo phosphorylation site mapping in mouse cardiac troponin I by high resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated. Biochemistry 48:8161–8170. doi:10.1021/bi900739f

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Bielawska A, Crane HM, Liotta D, Obeid LM, Hannun YA (1993) Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide. J Biol Chem 268:26226–26232

    CAS  PubMed  Google Scholar 

  3. Bowman JC, Steinberg SF, Jiang T, Geenen DL, Fishman GI, Buttrick PM (1997) Expression of protein kinase C beta in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest 100:2189–2195. doi:10.1172/JCI119755

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Brenner B (1988) Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction. Proc Natl Acad Sci USA 85:3265–3269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Brutsaert DL, Sys SU (1989) Relaxation and diastole of the heart. Physiol Rev 69:1228–1315

    CAS  PubMed  Google Scholar 

  6. Burkart EM, Sumandea MP, Kobayashi T, Nili M, Martin AF, Homsher E, Solaro RJ (2003) Phosphorylation or glutamic acid substitution at protein kinase C sites on cardiac troponin I differentially depress myofilament tension and shortening velocity. J Biol Chem 278:11265–11272. doi:10.1074/jbc.M210712200

    Article  CAS  PubMed  Google Scholar 

  7. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE (2001) A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107:813–822. doi:10.1172/JCI10947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Chokshi A, Drosatos K, Cheema FH, Ji R, Khawaja T, Yu S, Kato T, Khan R, Takayama H, Knoll R, Milting H, Chung CS, Jorde U, Naka Y, Mancini DM, Goldberg IJ, Schulze PC (2012) Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 125:2844–2853. doi:10.1161/CIRCULATIONAHA.111.060889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Coulton AT, Stelzer JE (2012) Cardiac myosin binding protein C and its phosphorylation regulate multiple steps in the cross-bridge cycle of muscle contraction. Biochemistry 51:3292–3301. doi:10.1021/bi300085x

    Article  CAS  PubMed  Google Scholar 

  10. D’Alessandro ME, Chicco A, Lombardo YB (2008) Dietary fish oil reverses lipotoxicity, altered glucose metabolism, and nPKCepsilon translocation in the heart of dyslipemic insulin-resistant rats. Metabolism 57:911–919. doi:10.1016/j.metabol.2008.02.005

    Article  PubMed  Google Scholar 

  11. de Tombe PP, Belus A, Piroddi N, Scellini B, Walker JS, Martin AF, Tesi C, Poggesi C (2007) Myofilament calcium sensitivity does not affect cross-bridge activation-relaxation kinetics. Am J Physiol Regul Integr Comp Physiol 292:R1129–R1136. doi:10.1152/ajpregu.00630.2006

    Article  PubMed  Google Scholar 

  12. Drosatos K, Bharadwaj KG, Lymperopoulos A, Ikeda S, Khan R, Hu Y, Agarwal R, Yu S, Jiang H, Steinberg SF, Blaner WS, Koch WJ, Goldberg IJ (2011) Cardiomyocyte lipids impair beta-adrenergic receptor function via PKC activation. Am J Physiol Endocrinol Metab 300:E489–E499. doi:10.1152/ajpendo.00569.2010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Edman KA, Mattiazzi AR (1981) Effects of fatigue and altered pH on isometric force and velocity of shortening at zero load in frog muscle fibres. J Muscle Res Cell Motil 2:321–334

    Article  CAS  PubMed  Google Scholar 

  14. Ferreira LF, Moylan JS, Gilliam LA, Smith JD, Nikolova-Karakashian M, Reid MB (2010) Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue. Am J Physiol Cell Physiol 299:C552–C560. doi:10.1152/ajpcell.00065.2010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ferreira LF, Moylan JS, Stasko S, Smith JD, Campbell KS, Reid MB (2012) Sphingomyelinase depresses force and calcium sensitivity of the contractile apparatus in mouse diaphragm muscle fibers. J Appl Physiol 112:1538–1545. doi:10.1152/japplphysiol.01269.2011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 100:1226–1231. doi:10.1073/pnas.0336724100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Florea S, Anjak A, Cai WF, Qian J, Vafiadaki E, Figueria S, Haghighi K, Rubinstein J, Lorenz J, Kranias EG (2012) Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging. Basic Res Cardiol 107:279. doi:10.1007/s00395-012-0279-z

    Article  PubMed Central  PubMed  Google Scholar 

  18. Gordon AM, Huxley AF, Julian FJ (1966) The variation in isometric tension with sarcomere length in vertebrate muscle fibres. J Physiol 184:170–192

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859. doi:10.1126/science.274.5294.1855

    Article  CAS  PubMed  Google Scholar 

  20. Hannun YA, Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol 10:73–80. doi:10.1016/S0962-8924(99)01694-3

    Article  CAS  PubMed  Google Scholar 

  21. Harrison SM, Bers DM (1990) Modification of temperature dependence of myofilament Ca sensitivity by troponin C replacement. Am J Physiol 258:C282–C288

    CAS  PubMed  Google Scholar 

  22. Hartman TJ, Martin JL, Solaro RJ, Samarel AM, Russell B (2009) CapZ dynamics are altered by endothelin-1 and phenylephrine via PIP2- and PKC-dependent mechanisms. Am J Physiol Cell Physiol 296:C1034–C1039. doi:10.1152/ajpcell.00544.2008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hinken AC, Hanft LM, Scruggs SB, Sadayappan S, Robbins J, Solaro RJ, McDonald KS (2012) Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A. J Muscle Res Cell Motil 33:439–448. doi:10.1007/s10974-012-9294-9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Huxley AF (1957) Muscle structure and theories of contraction. Prog Biophys Biophys Chem 7:255–318

    CAS  PubMed  Google Scholar 

  25. Jideama NM, Noland TA Jr, Raynor RL, Blobe GC, Fabbro D, Kazanietz MG, Blumberg PM, Hannun YA, Kuo JF (1996) Phosphorylation specificities of protein kinase C isozymes for bovine cardiac troponin I and troponin T and sites within these proteins and regulation of myofilament properties. J Biol Chem 271:23277–23283

    Article  CAS  PubMed  Google Scholar 

  26. Kirk JA, MacGowan GA, Evans C, Smith SH, Warren CM, Mamidi R, Chandra M, Stewart AF, Solaro RJ, Shroff SG (2009) Left ventricular and myocardial function in mice expressing constitutively pseudophosphorylated cardiac troponin I. Circ Res 105:1232–1239. doi:10.1161/CIRCRESAHA.109.205427

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Kobayashi T, Solaro RJ (2005) Calcium, thin filaments, and the integrative biology of cardiac contractility. Annu Rev Physiol 67:39–67. doi:10.1146/annurev.physiol.67.040403.114025

    Article  CAS  PubMed  Google Scholar 

  28. Kooij V, Boontje N, Zaremba R, Jaquet K, dos Remedios C, Stienen GJ, van der Velden J (2010) Protein kinase C alpha and epsilon phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium. Basic Res Cardiol 105:289–300. doi:10.1007/s00395-009-0053-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Layland J, Grieve DJ, Cave AC, Sparks E, Solaro RJ, Shah AM (2004) Essential role of troponin I in the positive inotropic response to isoprenaline in mouse hearts contracting auxotonically. J Physiol 556:835–847. doi:10.1113/jphysiol.2004.061176

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Lee SY, Kim JR, Hu Y, Khan R, Kim SJ, Bharadwaj KG, Davidson MM, Choi CS, Shin KO, Lee YM, Park WJ, Park IS, Jiang XC, Goldberg IJ, Park TS (2012) Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction. J Biol Chem 287:18429–18439. doi:10.1074/jbc.M111.296947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Lester JW, Hofmann PA (2000) Role for PKC in the adenosine-induced decrease in shortening velocity of rat ventricular myocytes. Am J Physiol Heart Circ Physiol 279:H2685–H2693

    CAS  PubMed  Google Scholar 

  32. Liu SJ, Kennedy RH (2003) Positive inotropic effect of ceramide in adult ventricular myocytes: mechanisms dissociated from its reduction in Ca2+ influx. Am J Physiol Heart Circ Physiol 285:H735–H744. doi:10.1152/ajpheart.01098.2002

    CAS  PubMed  Google Scholar 

  33. Liu WS, Heckman CA (1998) The sevenfold way of PKC regulation. Cell Signal 10:529–542. doi:10.1016/S0898-6568(98)00012-6

    Article  CAS  PubMed  Google Scholar 

  34. Mohamed AS, Dignam JD, Schlender KK (1998) Cardiac myosin-binding protein C (MyBP-C): identification of protein kinase A and protein kinase C phosphorylation sites. Arch Biochem Biophys 358:313–319. doi:10.1006/abbi.1998.0857

    Article  CAS  PubMed  Google Scholar 

  35. Montgomery DE, Chandra M, Huang Q, Jin J, Solaro RJ (2001) Transgenic incorporation of skeletal TnT into cardiac myofilaments blunts PKC-mediated depression of force. Am J Physiol Heart Circ Physiol 280:H1011–H1018

    CAS  PubMed  Google Scholar 

  36. Noland TA Jr, Guo X, Raynor RL, Jideama NM, Averyhart-Fullard V, Solaro RJ, Kuo JF (1995) Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca(2+)-stimulated MgATPase of reconstituted actomyosin S-1. J Biol Chem 270:25445–25454

    Article  CAS  PubMed  Google Scholar 

  37. Noland TA Jr, Kuo JF (1991) Protein kinase C phosphorylation of cardiac troponin I or troponin T inhibits Ca2(+)-stimulated actomyosin MgATPase activity. J Biol Chem 266:4974–4978

    CAS  PubMed  Google Scholar 

  38. Noland TA Jr, Kuo JF (1992) Protein kinase C phosphorylation of cardiac troponin T decreases Ca(2+)-dependent actomyosin MgATPase activity and troponin T binding to tropomyosin-F-actin complex. Biochem J 288(Pt 1):123–129

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Noland TA Jr, Raynor RL, Jideama NM, Guo X, Kazanietz MG, Blumberg PM, Solaro RJ, Kuo JF (1996) Differential regulation of cardiac actomyosin S-1 MgATPase by protein kinase C isozyme-specific phosphorylation of specific sites in cardiac troponin I and its phosphorylation site mutants. Biochemistry 35:14923–14931. doi:10.1021/bi9616357

    Article  CAS  PubMed  Google Scholar 

  40. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, Goldberg IJ (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 49:2101–2112. doi:10.1194/jlr.M800147-JLR200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Pellieux C, Montessuit C, Papageorgiou I, Pedrazzini T, Lerch R (2012) Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice. Am J Physiol Heart Circ Physiol 302:H1795–H1805. doi:10.1152/ajpheart.01023.2011

    Article  CAS  PubMed  Google Scholar 

  42. Puceat M, Clement O, Lechene P, Pelosin JM, Ventura-Clapier R, Vassort G (1990) Neurohormonal control of calcium sensitivity of myofilaments in rat single heart cells. Circ Res 67:517–524

    Article  CAS  PubMed  Google Scholar 

  43. Puglisi JL, Bassani RA, Bassani JW, Amin JN, Bers DM (1996) Temperature and relative contributions of Ca transport systems in cardiac myocyte relaxation. Am J Physiol 270:H1772–H1778

    CAS  PubMed  Google Scholar 

  44. Pyle WG, Chen Y, Hofmann PA (2003) Cardioprotection through a PKC-dependent decrease in myofilament ATPase. Am J Physiol Heart Circ Physiol 285:H1220–H1228. doi:10.1152/ajpheart.00076.2003

    CAS  PubMed  Google Scholar 

  45. Pyle WG, Sumandea MP, Solaro RJ, De Tombe PP (2002) Troponin I serines 43/45 and regulation of cardiac myofilament function. Am J Physiol Heart Circ Physiol 283:H1215–H1224. doi:10.1152/ajpheart.00128.2002

    CAS  PubMed  Google Scholar 

  46. Relling DP, Hintz KK, Ren J (2003) Acute exposure of ceramide enhances cardiac contractile function in isolated ventricular myocytes. Br J Pharmacol 140:1163–1168. doi:10.1038/sj.bjp.0705510

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Reuter H, Seuthe K, Korkmaz Y, Gronke S, Hoyer DP, Rottlaender D, Zobel C, Addicks K, Hoyer J, Grimminger P, Brabender J, Wilkie TM, Erdmann E (2012) The G protein Galpha11 is essential for hypertrophic signalling in diabetic myocardium. Int J Cardiol. doi:10.1016/j.ijcard.2012.04.039

    PubMed  Google Scholar 

  48. Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J (2011) A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res 109:141–150. doi:10.1161/CIRCRESAHA.111.242560

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW 2nd, Klevitsky R, Seidman CE, Seidman JG, Robbins J (2005) Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res 97:1156–1163. doi:10.1161/01.RES.0000190605.79013.4d

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Sancho Solis R, Ge Y, Walker JW (2008) Single amino acid sequence polymorphisms in rat cardiac troponin revealed by top-down tandem mass spectrometry. J Muscle Res Cell Motil 29:203–212. doi:10.1007/s10974-009-9168-y

    Article  CAS  PubMed  Google Scholar 

  51. Scruggs SB, Walker LA, Lyu T, Geenen DL, Solaro RJ, Buttrick PM, Goldspink PH (2006) Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation. J Mol Cell Cardiol 40:465–473. doi:10.1016/j.yjmcc.2005.12.009

    Article  CAS  PubMed  Google Scholar 

  52. Shattock MJ, Bers DM (1987) Inotropic response to hypothermia and the temperature-dependence of ryanodine action in isolated rabbit and rat ventricular muscle: implications for excitation-contraction coupling. Circ Res 61:761–771

    Article  CAS  PubMed  Google Scholar 

  53. Sheehan KA, Arteaga GM, Hinken AC, Dias FA, Ribeiro C, Wieczorek DF, Solaro RJ, Wolska BM (2011) Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis. J Mol Cell Cardiol 50:442–450. doi:10.1016/j.yjmcc.2010.10.032

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Solaro RJ (2008) Multiplex kinase signaling modifies cardiac function at the level of sarcomeric proteins. J Biol Chem 283:26829–26833. doi:10.1074/jbc.R800037200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Strang KT, Moss RL (1995) Alpha 1-adrenergic receptor stimulation decreases maximum shortening velocity of skinned single ventricular myocytes from rats. Circ Res 77:114–120

    Article  CAS  PubMed  Google Scholar 

  56. Sumandea MP, Pyle WG, Kobayashi T, de Tombe PP, Solaro RJ (2003) Identification of a functionally critical protein kinase C phosphorylation residue of cardiac troponin T. J Biol Chem 278:35135–35144. doi:10.1074/jbc.M306325200

    Article  CAS  PubMed  Google Scholar 

  57. Takeishi Y, Ping P, Bolli R, Kirkpatrick DL, Hoit BD, Walsh RA (2000) Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res 86:1218–1223

    Article  CAS  PubMed  Google Scholar 

  58. Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL (2008) Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res 103:974–982. doi:10.1161/CIRCRESAHA.108.177683

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Warren CM, Arteaga GM, Rajan S, Ahmed RP, Wieczorek DF, Solaro RJ (2008) Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant (Glu54Lys) linked to dilated cardiomyopathy. Proteomics 8:100–105. doi:10.1002/pmic.200700772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Watts JD, Gu M, Patterson SD, Aebersold R, Polverino AJ (1999) On the complexities of ceramide changes in cells undergoing apoptosis: lack of evidence for a second messenger function in apoptotic induction. Cell Death Differ 6:105–114. doi:10.1038/sj.cdd.4400472

    Article  CAS  PubMed  Google Scholar 

  61. Weith A, Sadayappan S, Gulick J, Previs MJ, Vanburen P, Robbins J, Warshaw DM (2012) Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain. J Mol Cell Cardiol 52:219–227. doi:10.1016/j.yjmcc.2011.09.019

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Wolska BM, Kitada Y, Palmiter KA, Westfall MV, Johnson MD, Solaro RJ (1996) CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction. Am J Physiol 270:H24–H32

    CAS  PubMed  Google Scholar 

  63. Wu G, Toyokawa T, Hahn H, Dorn GW 2nd (2000) Epsilon protein kinase C in pathological myocardial hypertrophy. Analysis by combined transgenic expression of translocation modifiers and Galphaq. J Biol Chem 275:29927–29930. doi:10.1074/jbc.C000380200

    Article  CAS  PubMed  Google Scholar 

  64. Young LH, Balin BJ, Weis MT (2005) Go 6983: a fast acting protein kinase C inhibitor that attenuates myocardial ischemia/reperfusion injury. Cardiovasc Drug Rev 23:255–272. doi:10.1111/j.1527-3466.2005.tb00170.x

    Article  CAS  PubMed  Google Scholar 

  65. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, Youker KA, Taegtmeyer H (2002) Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 51:2587–2595

    Article  CAS  PubMed  Google Scholar 

  66. Zhang J, Dong X, Hacker TA, Ge Y (2010) Deciphering modifications in swine cardiac troponin I by top-down high-resolution tandem mass spectrometry. J Am Soc Mass Spectrom 21:940–948. doi:10.1016/j.jasms.2010.02.005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97:1784–1789. doi:10.1073/pnas.97.4.1784

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Dr. Suresh Govidan and Dr. Xiang Ji for their technical assistance with the cMyBP-C immunoblots. This research was supported by an American Heart Association, Midwest Affiliate pre-doctoral fellowship to JNS, NIH research grants R01 HL-64035 (RJS and BMW), R01 HL-105826 and K02 HL-114749 (SS), RO1 HL-081680 (DFW), and PO1 HL-62426 (Project 1 and Core C to RJS and CMW).

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Simon, J.N., Chowdhury, S.A.K., Warren, C.M. et al. Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation. Basic Res Cardiol 109, 445 (2014). https://doi.org/10.1007/s00395-014-0445-6

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