Differences in Sarcoplasmic Reticulum Ca(superscript 2+) Leak Characteristics between Systolic and Diastolic Heart Failure Rabbit Models

10.4077/CJP.2011.AMM070

Lei Wang；Shi-Jie Zhang；Cao Zou；Zhi-Hua Liu

systolic heart failure ； diastolic heart failure ； Ca(superscript 2+) leak ； ryanodine receptor ； phosphorylation

The Chinese Journal of Physiology

54卷2期（2011 / 04 / 01）

133 - 142

英文

Diastolic heart failure (DHF) and systolic heart failure (SHF) are two clinical subsets of chronic heart failure (CHF). Sarcoplasmic reticulum (SR) Ca(superscript 2+) leak has been measured in SHF and might contribute to contractile dysfunction and arrhythmogenesis. However, no study has investigated a similar phenomenon in DHF. Thus, we established DHF and SHF rabbit models and compared the differences in Ca(superscript 2+) leak between these models. New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group and SHF group. Cardiac functions were determined by echocardiography and hemodynamic assays. The SR Ca(superscript 2+) leak was measured with a calcium-imaging device and the expression and activities of related proteins were evaluated with Western blots and autophosphorylation. In the DHF group, there was significantly increased ventricular wall thickness and stiffness, reduced diastolic function, and total amount of FK-506 binding protein 12.6 (FKBP12.6), increased expression and activity of protein kinase A (PKA) and phosphorylation site (P2809) in the ryanodine receptor (RyR2), but no prominent Ca(superscript 2+) leak. In the SHF group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca(superscript 2+) leak, reduced total amount of FKBP12.6 and FKBP12.6-RyR2 association, increased expression and activity of PKA and Ca(superscript 2+)/calmodulin-dependent protein kinase II (CaMKII) and their RyR2 phosphorylation sites with unchanged P2030. Our results suggest that a prominent SR Ca(superscript 2+) leak was not observed in the DHF model, which may provide a new idea for the reasons in preserved systolic function, and CaMKII possibly plays a more important role in SR Ca(superscript 2+) leak.

1. Ai, X.,Curran, J. W.,Shannon, T. R.,Bers, D. M.,Pogwizd, S. M.(2005).Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure.Circ. Res.,97,1314-1322.
2. Aurigemma, G. P.,Zile, M. R.,Gasch, W. H.(2006).Contractile behavior of the left ventricle in diastolic heart failure.Circulation,113,296-304.
3. Baicu, C. F.,Zile, M. R.,Aurigemma, G. P.,Gaasch, W. H.(2005).Left ventricular systolic performance, function and contractility in patients with diastolic heart failure.Circulation,111,2306-2312.
4. Bhatia, R. S.,Tu, J. V.,Lee, D. S.,Austin, P. C.,Fang, J.,Haouzi, A.,Gong, Y.,Liu, P. P.(2006).Outcome of heart failure with preserved ejection fraction in a population-based study.N. Engl. J. Med.,355,260-269.
5. Curran, J.,Hinton, M. J.,Rios, E.,Bers, D. M.,Shannon, T. R.(2007).Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase.Circ. Res.,100,391-398.
6. Doi, M.,Yano, M.,Kobayashi, S.,Kohno, M.,Tokuhisa, T.,Okuda, S.,Suetsugu, M.,Hisamatsu, Y.,Ohkusa, T.,Kohno, M.,Matsuzaki, M.(2002).Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor.Circulation,105,1374-1379.
7. Duan, D. D.(2010).A leakage leads to failure: roles of sarcoplasmic reticulum Ca2+ leak via RyR2 in heart failure progression.Hypertension,55,849-851.
8. Fill, M. ,Copello, J. A.(2002).Ryanodine receptor calcium release channels.Physiol. Rev.,82,893-922.
9. George, C. H.(2008).Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance?.Cardiovasc Res.,77,302-314.
10. Goueli, B. S.,Hsiao, K.,Tereba, A.,Goueli, S. A.(1995).A novel and simple method to assay the activity of individual protein kinases in a crude tissue extract.Anal. Biochem.,225,10-17.
11. Guo, T.,Cornea, R. L.,Huke, S.,Camors, E.,Yang, Y.,Picht, E.,Freun, B. R.,Bers, D. M.(2010).Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and the effects on Ca sparks.Circ. Res.,106,1743-1752.
12. Guo, T.,Zhang, T.,Mestril, R.,Bers, D. M.(2006).Ca2+/Calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes.Circ. Res.,99,398-406.
13. Hogg, K.,Swedberg, K.,McMurray, J.(2004).Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis.J. Am. Coll. Cardiol.,43,317-327.
14. Huang, F.,Shan, J.,Reiken, S.,Wehrens, X. H.,Marks, A. R.(2006).Analysis of calstabin-2 (FKBP12.6)-ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice.Proc. Natl. Acad. Sci.,103,3456-3461.
15. Huke, S.,Bers, D. M.(2008).Ryanodine receptor phosphorylation at Serine 2030, 2808 and 2814 in rat cardiomyocytes.Biochem. Biophys. Res. Commun.,376,80-85.
16. Jones, P. P.,Meng, X.,Xiao, B.,Cai, S.,Bolstad, J.,Wagenknecht, T.,Liu, Z.,Chen, S. R.(2008).Localization of PKA phosphorylation site, Ser(2030), in the three-dimensional structure of cardiac ryanodine receptor.Biochem. J.,410,261-270.
17. Katz, A. M.,Zile, M. R.(2006).New molecular mechanism in diastolic heart failure.Circulation,113,1922-1925.
18. Kawai, M.,Konishi, M.(1994).Measurement of sarcoplasmic reticulum calcium content in skinned mammalian cardiac muscle.Cell Calcium.,16,123-136.
19. Kitzman, D. W.,Little, W. C.,Brubaker, P. H,Anderson, R. T.,Hundley, W. G.,Marburger, C. T.,Brosnihan, B.,Morgan, T. M.,Stewart, K. P.(2002).Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure.J. Am. Med. Assoc.,288,2144-2150.
20. Konstam, M. A.(2003)."Systolic and diastolic dysfunction" in heart failure? Time for a new paradigm.J. Card. Fail.,9,1-3.
21. Kranias, E. G.,Schwartz, A.,Jungmann, R. A.(1982).Characterization of cyclic 3':5'-amp-dependent protein kinase in sarcoplasmic reticulum and cytosol of canine myocardium.Biochim. Biophys. Acta,709,28-37.
22. Lehnart, S. E.,Terrenoire, C.,Reiken, S.,Wehrens, X. H.,Song, L. S.,Tillman, E. J.,Mancarella, S.,Coromilas, J.,Lederer, W. J.,Kass, R. S.,Marks, A. R.(2006).Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.Proc. Natl. Acad. Sci. U.S.A.,103,7906-7910.
23. Li, Y.,Kranias, E. G.,Mignery, G. A.,Bers, D. M.(2002).Protein kinase A phosphorylation of the ryanodine receptor does not affect Ca sparks in permeabilized mouse ventricular myocytes.Circ. Res.,90,309-316.
24. Mackiewicz, U.,Lewartowski, B.(2008).The effect of sarcoplasmic reticulum Ca2+ leak on contractile activity of guinea pig heart myocytes depends in activity of sarcoplasmic reticulum Ca2+-ATPase and Na+/Ca2+ exchanger.J. Physiol. Pharmacol.,59,287-300.
25. Maier, L. S.,Zhang, T.,Chen, L.,DeSantiago, J.,Brown, J. H.,Bers, D. M.(2003).Transgenic CaMKIIδc overexpression uniquely alters cardiac myocyte Ca handling: reduced SR Ca load and activated SR Ca release.Circ. Res.,92,904-911.
26. Marx, S. O.,Reiken, S.,Hisamatsu, Y.,Jayaraman, T.,Burkhoff, D.,Rosemblit, N.,Marks, A. R.(2000).PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.Cell,101,365-376.
27. Morimoto, S.,O-Uchi, J.,Kawai, M.,Hoshina, T.,Kusakari, Y.,Komukai, K.,Sasaki, H.,Hongo, K.,Kurihara, S.(2009).Protein kinase A-dependent phosphorylation of ryanodine receptors increases Ca2+ leak in mouse heart.Biochem. Biophys. Res. Commun.,390,87-92.
28. Ono, M.,Yano, M.,Hino, A.,Suetomi, T.,Xu, X.,Susa, T.,Uchinoumi, H.,Tateishi, H.,Oda, T.,Okuda, S.,Doi, M.,Kobayashi, S.,Yamamoto, T.,Koseki, N.,Kyushiki, H.,Ikemoto, N.,Matsuzaki, M.(2010).Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure.Cardiovasc. Res.,13,1-24.
29. Owan, T. E.,Hodge, D. O.,Herges, R. M.,Jacobsen, S. J.,Roger, V. L.,Redfield, M. M.(2006).Trends in prevalence and outcome of heart failure with preserved ejection fraction.N. Engl. J. Med.,355,251-259.
30. Prestle, J.,Janssen, P. M.,Janssen, A. P.,Zeitz, O.,Lehnart, S. E.,Bruce, L.,Smith, G. L.,Hasenfuss, G.(2001).Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-mediated Ca(2+) leak from the sarcoplasmic reticulum and increases contractility.Circ. Res.,88,188-194.
31. Reiken, S.,Wehrens, X. H.,Vest, J. A.,Barbone, A.,Klotz, S.,Mancini, D.,Burkhoff, D.,Marks, A. R.(2003).Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure.Circulation,107,2459-2466.
32. Rodriguez, P.,Bhogal, M. S.,Colyer, J.(2003).Stoichiometric phosphorylation of cardiac ryanodine receptor on serine 2809 by calmodulin-dependent kinase II and protein kinase A.J. Biol. Chem.,278,38593-38600.
33. Su, Z.,Sugishita, K.,Li, F.,Ritter, M.,Barry, W. H.(2003).Effects of FK506 on [Ca2+]i differ in mouse and rabbit ventricular myocytes.J. Pharmacol. Exp. Ther.,304,334-341.
34. Tateishi, H.,Yano, M.,Mochizuki, M.,Suetomi, T.,Ono, M.,Xu, X.,Uchinoumi, H.,Okuda, S.,Oda, T.,Kobayashi, S.,Yamamoto, T.,Ikeda, Y.,Ohkusa, T.,Ikemoto, N.,Matsuzaki, M.(2009).Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts.Cardiovasc. Res.,81,536-545.
35. Terentyev, D.,Belevych, A. E.,Terentyeva, R.,Martin, M. M.,Malana, G. E.,Kuhn, D. E.,Abdellatif, M.,Feldman, D. S.,Elton, T. S.,Gyorke, S.(2009).miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2.Circ. Res.,104,514-521.
36. Terentyev, D.,Gyorke, I.,Belevych, A. E.,Terentyeva, R.,Sridhar, A.,Nishijima, Y.,de Blanco, E. C.,Khanna, S.,Sen, C. K.,Cardounel, A. J.,Carnes, C. A.,Gyorke, S.(2008).Redox modification of ryanodine receptors contributes to sarcoplasmic reticulum Ca2+ leak in chronic heart failure.Circ. Res.,103,1466-1472.
37. van Heerebeek, L.,Borbely, A.,Niessen, H. W.,Bronzwaer, J. G.,van der Velden, J.,Stienen, G. J.,Linke, W. A.,Laarman, G. J.,Paulus, W. J.(2006).Myocardial structure and function differ in systolic and diastolic heart failure.Circulation,113,1966-1973.
38. Vinereanu, D.,Nicolaides, E.,Tweddel, A. C.,Fraser, A. G.(2005)."Pure" diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure.Eur. J. Heart Fail.,7,820-828.
39. Wang, J.,Kurrelmeyer, K. M.,Torre-Amione, N.,Nagueh, S. F.(2007).Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy.J. Am. Coll. Cardiol.,49,88-96.
40. Wehrens, X. H.,Lehnart, S. E.,Huang, F.,Vest, J. A.,Reiken, S. R.,Mohler, P. J.,Sun, J.,Guatimosim, S.,Song, L. S.,Rosemblit, N.,D''Armiento, J. M.,Napolitano, C.,Memmi, M.,Priori, S. G.,Lederer, W. J.,Marks, A. R.(2003).FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.Cell,113,829-840.
41. Wehrens, X. H.,Lehnart, S. E.,Reiken, S. R.,Marks, A. R.(2004).Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor.Circ. Res.,94,e61-e70.
42. Xiao, B.,Jiang, M. T.,Zhao, M.,Yang, D.,Sutherland, C.,Lai, F. A.,Walsh, M. P.,Warltier, D. C.,Cheng, H.,Chen, S. R.(2005).Characterization of a novel PKA phosphorylation site, serine-2030, reveals no PKA hyperphosphorylation of the cardiac ryanodine receptor in canine heart failure.Circ. Res.,96,847-855.
43. Xiao, B.,Sutherland, C.,Walsh, M. P.,Chen, S. R.(2004).Protein kinase A phosphorylation at serine-2808 of the cardiac Ca2+-release channel does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6).Circ. Res.,94,487-495.
44. Xiao, J.,Tian, X.,Jones, P. P.,Bolstad, J.,Kong, H.,Wang, R.,Zhang, L.,Duff, H. J.,Gillis, A. M.,Fleischer, S.,Kotlikoff, M.,Copello, J. A.,Chen, S. R.(2007).Removal of FKBP12.6 does not alter the conductance and activation of the cardiac ryanodine receptor or the susceptibility to stress-induced ventricular arrhythmias.J. Biol. Chem.,282,34828-34838.
45. Xiao, R. P.,Valdivia, H. H.,Bogdanov, K.,Valdivia, C.,Lakatta, E. G.,Cheng, H.(1997).The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart.J. Physiol.,500,343-354.
46. Yano, M.,Ono, K.,Ohkusa, T.,Suetsugu, M.,Kohno, M.,Hisaoka, T.,Kobayashi, S.,Hisamatsu, Y.,Yamamoto, T.,Kohno, M.,Noguchi, N.,Takasawa, S.,Okamoto, H.,Matsuzaki, M.(2000).Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure.Circulation,102,2131-2136.
47. Zile, M. R.,Brutsaert, D. L.(2002).New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function.Circulation,105,1387-1393.

1. Wu, Chieh-Hsi,Shen, Chia-Yao,Pai, Peiying,Huang, Chih-Yang,Hsieh, You-Liang,Ho, Tsung-Jung,Fan, Ming-Jen,Day, Cecilia Hsuan,Chung, Li-Chin,Cheng, Yi-Chang(2014).Effects of Garlic Oil on Interleukin-6 Mediated Cardiac Hypertrophy in Hypercholesterol-Fed Hamsters.中國生理學雜誌,57(6),320-328.