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Targeted ablation of the histidine-rich Ca2+-binding protein (HRC) gene is associated with abnormal SR Ca2+-cycling and severe pathology under pressure-overload stress

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Abstract

The histidine-rich Ca2+-binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) and exhibits high-capacity Ca2+-binding properties. Overexpression of HRC in the heart resulted in impaired SR Ca2+ uptake and depressed relaxation through its interaction with SERCA2a. However, the functional significance of HRC in overall regulation of calcium cycling and contractility is not currently well defined. To further elucidate the role of HRC in vivo under physiological and pathophysiological conditions, we generated and characterized HRC-knockout (KO) mice. The KO mice were morphologically and histologically normal compared to wild-type (WT) mice. At the cellular level, ablation of HRC resulted in significantly enhanced contractility, Ca2+ transients, and maximal SR Ca2+ uptake rates in the heart. However, after-contractions were developed in 50 % of HRC-KO cardiomyocytes, compared to 11 % in WT mice under stress conditions of high-frequency stimulation (5 Hz) and isoproterenol application. A parallel examination of the electrical activity revealed significant increases in the occurrence of Ca2+ spontaneous SR Ca2+ release and delayed afterdepolarizations with ISO in HRC-KO, compared to WT cells. The frequency of Ca2+ sparks was also significantly higher in HRC-KO cells with ISO, consistent with the elevated SR Ca2+ load in the KO cells. Furthermore, HRC-KO cardiomyocytes showed significantly deteriorated cell contractility and Ca2+-cycling caused possibly by depressed SERCA2a expression after transverse-aortic constriction (TAC). Also HRC-null mice exhibited severe cardiac hypertrophy, fibrosis, pulmonary edema and decreased survival after TAC. Our results indicate that ablation of HRC is associated with poorly regulated SR Ca2+-cycling, and severe pathology under pressure-overload stress, suggesting an essential role of HRC in maintaining the integrity of cardiac function.

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References

  1. Arvanitis DA, Sanoudou D, Kolokathis F, Vafiadaki E, Papalouka V, Kontrogianni-Konstantopoulos A, Theodorakis GN, Paraskevaidis IA, Adamopoulos S, Dorn GW 2nd, Kremastinos DT, Kranias EG (2008) The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy. Eur Heart J 29:2514–2525. doi:10.1093/eurheartj/ehn328

    Article  PubMed  CAS  Google Scholar 

  2. Arvanitis DA, Vafiadaki E, Fan GC, Mitton BA, Gregory KN, Del Monte F, Kontrogianni-Konstantopoulos A, Sanoudou D, Kranias EG (2007) Histidine-rich Ca2+-binding protein interacts with sarcoplasmic reticulum Ca2+–ATPase. Am J Physiol Heart Circ Physiol 293:H1581–H1589. doi:10.1152/ajpheart.00278.2007

    Article  PubMed  CAS  Google Scholar 

  3. Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49. doi:10.1146/annurev.physiol.70.113006.100455

    Article  PubMed  CAS  Google Scholar 

  4. Bers DM, Guo T (2005) Calcium signaling in cardiac ventricular myocytes. Ann N Y Acad Sci 1047:86–98. doi:10.1196/annals.1341.008

    Article  PubMed  CAS  Google Scholar 

  5. Brittsan AG, Kranias EG (2000) Phospholamban and cardiac contractile function. J Mol Cell Cardiol 32:2131–2139. doi:10.1006/jmcc.2000.1270

    Article  PubMed  CAS  Google Scholar 

  6. Cha H, Kim JM, Oh JG, Jeong MH, Park CS, Park J, Jeong HJ, Park BK, Lee YH, Jeong D, Yang DK, Bernecker OY, Kim DH, Hajjar RJ, Park WJ (2008) PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility. J Mol Cell Cardiol 45(6):796–803. doi:10.1016/j.yjmcc.2008.09.124

    Article  PubMed  CAS  Google Scholar 

  7. Chopra N, Yang T, Asghari P, Moore ED, Huke S, Akin B, Cattolica RA, Perez CF, Hlaing T, Knollmann-Ritschel BE, Jones LR, Pessah IN, Allen PD (2009) Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias. Proc Natl Acad Sci USA 106:7636–7641. doi:10.1073/pnas.0902919106

    Article  PubMed  CAS  Google Scholar 

  8. Elliott EB, Hasumi H, Otani N, Matsuda T, Matsuda R, Kaneko N, Smith GL, Loughrey CM (2011) K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca2+ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes. Basic Res Cardiol 106:1009–1022. doi:10.1007/s00395-011-0218-4

    Article  PubMed  CAS  Google Scholar 

  9. Fan GC, Gregory KN, Zhao W, Park WJ, Kranias EG (2004) Regulation of myocardial function by histidine-rich, calcium-binding protein. Am J Physiol Heart Circ Physiol 287:H1705–H1711. doi:10.1152/ajpheart.01211.2003

    Article  PubMed  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Ginsburg KS, Bers DM (2004) Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and ICa trigger. J Physiol 556:463–480. doi:10.1113/jphysiol.2003.055384

    Article  PubMed  CAS  Google Scholar 

  12. Gregory KN, Ginsburg KS, Bodi I, Hahn H, Marreez YM, Song Q, Padmanabhan PA, Mitton BA, Waggoner JR, Del Monte F, Park WJ, Dorn GW 2nd, Bers DM, Kranias EG (2006) Histidine-rich Ca2+ binding protein: a regulator of sarcoplasmic reticulum calcium sequestration and cardiac function. J Mol Cell Cardiol 40:653–665. doi:10.1016/j.yjmcc.2006.02.003

    Article  PubMed  CAS  Google Scholar 

  13. Györke I, Hester N, Jones LR, Györke S (2004) The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J 86(4):2121–1218. doi:10.1016/S0006-3495(04)74271-X

    Google Scholar 

  14. Györke S, Terentyev D (2008) Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc Res 77:245–255. doi:10.1093/cvr/cvm038

    Article  PubMed  Google Scholar 

  15. Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37:279–289. doi:10.1016/S0008-6363(97)00277-0

    Article  PubMed  CAS  Google Scholar 

  16. Heinzel FR, Luo Y, Dodoni G, Boengler K, Petrat F, Di Lisa F, de Groot H, Schulz R, Heusch G (2006) Formation of reactive oxygen species at increased contraction frequency in rat cardiomyocytes. Cardiovasc Res 71(2):374–382. doi:10.1016/j.cardiores.2006.05.014

    Article  PubMed  CAS  Google Scholar 

  17. Heusch G (2011) Heart rate and heart failure. Circ J 75:229–236

    Article  PubMed  Google Scholar 

  18. Hofmann SL, Brown MS, Lee E, Pathak RK, Anderson RG, Goldstein JL (1989) Purification of a sarcoplasmic reticulum protein that binds Ca2+ and plasma lipoproteins. J Biol Chem 264:8260–8270

    PubMed  CAS  Google Scholar 

  19. Hofmann SL, Goldstein JL, Orth K, Moomaw CR, Slaughter CA, Brown MS (1989) Molecular cloning of a histidine-rich Ca2+-binding protein of sarcoplasmic reticulum that contains highly conserved repeated elements. J Biol Chem 264:18083–18090

    PubMed  CAS  Google Scholar 

  20. Hofmann SL, Topham M, Hsieh CL, Francke U (1991) cDNA and genomic cloning of HRC, a human sarcoplasmic reticulum protein, and localization of the gene to human chromosome 19 and mouse chromosome 7. Genomics 9:656–669. doi:10.1016/0888-7543(91)90359-M

    Article  PubMed  CAS  Google Scholar 

  21. Hong S, Kim TW, Choi I, Woo JM, Oh J, Park WJ, Kim DH, Cho C (2005) Complementary DNA cloning, genomic characterization and expression analysis of a mammalian gene encoding histidine-rich calcium binding protein. Biochim Biophys Acta 1727:188–196. doi:10.1016/j.bbaexp.2005.01.006

    Article  PubMed  CAS  Google Scholar 

  22. Jaehnig EJ, Heidt AB, Greene SB, Cornelissen I, Black BL (2006) Increased susceptibility to isoproterenol-induced cardiac hypertrophy and impaired weight gain in mice lacking the histidine-rich calcium-binding protein. Mol Cell Biol 26:9315–9326. doi:10.1128/MCB.00482-06

    Article  PubMed  CAS  Google Scholar 

  23. Kim E, Shin DW, Hong CS, Jeong D, Kim DH, Park WJ (2003) Increased Ca2+ storage capacity in the sarcoplasmic reticulum by overexpression of HRC (histidine-rich Ca2+ binding protein). Biochem Biophys Res Commun 300:192–196. doi:10.1016/S0006-291X(02)02829-2

    Article  PubMed  CAS  Google Scholar 

  24. Kranias EG, Bers DM (2007) Calcium and cardiomyopathies. Subcell Biochem 45:523–537. doi:10.1007/978-1-4020-6191-2_20

    Article  PubMed  CAS  Google Scholar 

  25. Lee HG, Kang H, Kim DH, Park WJ (2001) Interaction of HRC (histidine-rich Ca2+-binding protein) and triadin in the lumen of sarcoplasmic reticulum. J Biol Chem 276:39533–39538. doi:10.1074/jbc.M010664200

    Article  PubMed  CAS  Google Scholar 

  26. Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, Dalton ND, Peterson KL, Chen J, Bers DM, Brown JH (2009) Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest 119:1230–1240. doi:10.1172/JCI38022

    Article  PubMed  CAS  Google Scholar 

  27. Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG (1994) Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 75:401–409. doi:10.1161/01.RES.75.3.401

    Article  PubMed  CAS  Google Scholar 

  28. Oh JG, Jeong D, Cha H, Kim JM, Lifirsu E, Kim J, Yang DK, Park CS, Kho C, Park S, Yoo YJ, Kim DH, Kim J, Hajjar RJ, Park WJ (2012) PICOT increases cardiac contractility by inhibiting PKCζ activity. J Mol Cell Cardiol 53(1):53–63. doi:10.1016/j.yjmcc.2012.03.005

    Article  PubMed  CAS  Google Scholar 

  29. Oh JG, Kim J, Jang SP, Nguen M, Yang DK, Jeong D, Park ZY, Park SG, Hajjar RJ, Park WJ (2013) Decoy peptides targeted to protein phosphatase 1 inhibit dephosphorylation of phospholamban in cardiomyocytes. J Mol Cell Cardiol 56:63–71. doi:10.1016/j.yjmcc.2012.12.005

    Article  PubMed  CAS  Google Scholar 

  30. Pagani ED, Solaro RJ (1984) Coordination of cardiac myofibrillar and sarcotubular activities in rats exercised by swimming. Am J Physiol 247:H909–H915

    PubMed  CAS  Google Scholar 

  31. Park CS, Cha H, Kwon EJ, Jeong D, Hajjar RJ, Kranias EG, Cho C, Park WJ, Kim DH (2012) AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure. PLoS ONE 7(8):e43282. doi:10.1371/journal.pone.0043282

    Article  PubMed  CAS  Google Scholar 

  32. Piacentino V 3rd, Weber CR, Gaughan JP, Margulies KB, Bers DM, Houser SR (2002) Modulation of contractility in failing human myocytes by reverse-mode Na+/Ca2+ exchange. Ann N Y Acad Sci 976:466–471. doi:10.1111/j.1749-6632.2002.tb04776.x

    Article  PubMed  CAS  Google Scholar 

  33. Picello E, Damiani E, Margreth A (1992) Low-affinity Ca2+-binding sites versus Zn2+-binding sites in histidine-rich Ca2+-binding protein of skeletal muscle sarcoplasmic reticulum. Biochem Biophys Res Commun 186:659–667. doi:10.1016/0006-291X(92)90797-O

    Article  PubMed  CAS  Google Scholar 

  34. Puglisi JL, Bassani RA, Bassani JW, Amin JN, Bers DM (1996) Temperature and relative contributions of Ca2+ transport systems in cardiac myocyte relaxation. Am J Physiol 270:H1772–H1778

    PubMed  CAS  Google Scholar 

  35. Ramirez RJ, Sah R, Liu J, Rose RA, Backx PH (2011) Intracellular [Na+] modulates synergy between Na+/Ca2+ exchanger and L-type Ca2+ current in cardiac excitation-contraction coupling during action potentials. Basic Res Cardiol 106:967–977. doi:10.1007/s00395-011-0202-z

    Article  PubMed  CAS  Google Scholar 

  36. Ridgeway AG, Petropoulos H, Siu A, Ball JK, Skerjanc IS (1999) Cloning, tissue distribution, subcellular localization and overexpression of murine histidine-rich Ca2+ binding protein. FEBS Lett 456:399–402. doi:10.1016/S0014-5793(99)00993-X

    Article  PubMed  CAS  Google Scholar 

  37. Shah AM, Sauer H (2006) Transmitting biological information using oxygen: reactive oxygen species as signalling molecules in cardiovascular pathophysiology. Cardiovasc Res 71:191–194. doi:10.1016/j.cardiores.2006.05.018

    Article  PubMed  CAS  Google Scholar 

  38. Solaro RJ, Briggs FN (1974) Estimating the functional capabilities of sarcoplasmic reticulum in cardiac muscle. Calcium binding. Circ Res 34:531–540. doi:10.1161/01.RES.34.4.531

    Article  CAS  Google Scholar 

  39. Sossalla S, Maurer U, Schotola H, Hartmann N, Didié M, Zimmermann WH, Jacobshagen C, Wagner S, Maier LS (2011) Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIδC can be reversed by inhibition of late Na+ current. Basic Res Cardiol 106:263–272. doi:10.1007/s00395-010-0136-x

    Article  PubMed  CAS  Google Scholar 

  40. Terentyev D, Kubalova Z, Valle G, Nori A, Vedamoorthyrao S, Terentyeva R, Viatchenko-Karpinski S, Bers DM, Williams SC, Volpe P, Györke S (2008) Modulation of SR Ca2+ release by luminal Ca2+ and calsequestrin in cardiac myocytes: effects of CASQ2 mutations linked to sudden cardiac death. Biophys J 95:2037–2048. doi:10.1529/biophysj.107.128249

    Article  PubMed  CAS  Google Scholar 

  41. Terentyev D, Cala SE, Houle TD, Viatchenko-Karpinski S, Györke I, Terentyeva R, Williams SC, Györke S (2005) Triadin overexpression stimulates excitation-contraction coupling and increases predisposition to cellular arrhythmia in cardiac myocytes. Circ Res 96:651–658. doi:10.1161/01.RES.0000160609.98948.25

    Article  PubMed  CAS  Google Scholar 

  42. Toischer K, Lehnart SE, Tenderich G, Milting H, Körfer R, Schmitto JD, Schöndube FA, Kaneko N, Loughrey CM, Smith GL, Hasenfuss G, Seidler T (2010) K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum. Basic Res Cardiol 105:279–287. doi:10.1007/s00395-009-0057-8

    Article  PubMed  CAS  Google Scholar 

  43. van Heeswijk MP, Geertsen JA, van Os CH (1984) Kinetic properties of the ATP-dependent Ca2+ pump and the Na+/Ca2+ exchange system in basolateral membranes from rat kidney cortex. J Membr Biol 79:19–31. doi:10.1007/BF01868523

    Article  PubMed  Google Scholar 

  44. Viatchenko-Karpinski S, Terentyev D, Györke I, Terentyeva R, Volpe P, Priori SG, Napolitano C, Nori A, Williams SC, Györke S (2004) Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Circ Res 94:471–477. doi:10.1161/01.RES.0000115944.10681.EB

    Article  PubMed  CAS  Google Scholar 

  45. Vinet L, Pezet M, Bito V, Briec F, Biesmans L, Rouet-Benzineb P, Gellen B, Prévilon M, Chimenti S, Vilaine JP, Charpentier F, Sipido KR, Mercadier JJ (2012) Cardiac FKBP12.6 overexpression protects against triggered ventricular tachycardia in pressure overloaded mouse hearts. Basic Res Cardiol 107:246. doi:10.1007/s00395-012-0246-8

  46. Wang HS, Cohen IS (2003) Calcium channel heterogeneity in canine left ventricular myocytes. J Physiol 547:825–833. doi:10.1113/jphysiol.2002.035410

    Article  PubMed  CAS  Google Scholar 

  47. Wehrens XH (2007) Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias. Eur Heart J 28:1054–1056. doi:10.1093/eurheartj/ehm068

    Article  PubMed  CAS  Google Scholar 

  48. Zhang L, Kelley J, Schmeisser G, Kobayashi YM, Jones LR (1997) Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. J Biol Chem 272:23389–23397. doi:10.1074/jbc.272.37.23389

    Article  PubMed  CAS  Google Scholar 

  49. Zhao W, Yuan Q, Qian J, Waggoner JR, Pathak A, Chu G, Mitton B, Sun X, Jin J, Braz JC, Hahn HS, Marreez Y, Syed F, Pollesello P, Annila A, Wang HS, Schultz Jel J, Molkentin JD, Liggett SB, Dorn GW 2nd, Kranias EG (2006) The presence of Lys27 instead of Asn27 in human phospholamban promotes sarcoplasmic reticulum Ca2+–ATPase superinhibition and cardiac remodeling. Circulation 113:995–1004. doi:10.1161/CIRCULATIONAHA.105.583351

    Article  PubMed  CAS  Google Scholar 

  50. Zhou X, Fan GC, Ren X, Waggoner JR, Gregory KN, Chen G, Jones WK, Kranias EG (2007) Overexpression of histidine-rich Ca2+-binding protein protects against ischemia/reperfusion-induced cardiac injury. Cardiovasc Res 75:487–497. doi:10.1016/j.cardiores.2007.04.005

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Korean Systems Biology Research Grant M10503010001-06N0301-00110 (to D.H.K. and C.C.); GIST Systems Biology Infrastructure Establishment Grant (to D.H.K. and C.C.); National Institutes of Health Grants HL-48093 (to C.F.A), HL-26507 (to E.G.K.), HL-64018 and HL-77101 (to E.G.K.).

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju, 500-712, Republic of Korea

    Chang Sik Park, Hoyong Lee, Hyeseon Cha, Jae Gyun Oh, Sunghee Hong, Sora Jin, Inju Park, Woo Jin Park, Chunghee Cho & Do Han Kim

  2. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA

    Shan Chen, Peidong Han, Vivek P. Singh, Hong-Sheng Wang & Evangelia G. Kranias

  3. Department of Pharmacology, University of California Davis, Davis, CA, USA

    Kenneth S. Ginsburg & Donald M. Bers

  4. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA

    Clara Franzini-Armstrong

  5. Molecular Biology Division, Center for Basic Research, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece

    Evangelia G. Kranias

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  1. Chang Sik Park
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Correspondence to Evangelia G. Kranias, Chunghee Cho or Do Han Kim.

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C.S. Park, S. Chen and H. Lee contributed equally to this work.

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Park, C.S., Chen, S., Lee, H. et al. Targeted ablation of the histidine-rich Ca2+-binding protein (HRC) gene is associated with abnormal SR Ca2+-cycling and severe pathology under pressure-overload stress. Basic Res Cardiol 108, 344 (2013). https://doi.org/10.1007/s00395-013-0344-2

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