Skip to main content
SpringerLink
Log in

Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+ signal decay and muscle relaxation. Altered Ca2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+ handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca2+ reuptake was investigated by measuring Ca2+ dynamics and analyzing protein expression. Kinetic analysis of Ca2+ reuptake in electrically paced myocytes showed a ~ 21 ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca2+ reuptake resulted in a ~ 22 ms delay in Ca2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Data are available on request to the authors.

References

  1. Huizar JF, Ellenbogen KA, Tan AY, Kaszala K (2019) Arrhythmia-induced cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 73:2328–2344. https://doi.org/10.1016/j.jacc.2019.02.045

    Article  PubMed  PubMed Central  Google Scholar 

  2. Huizar JF, Ellenbogen KA (2020) Is PVC-induced cardiomyopathy truly reversible?: A deep dive into questions that remain unanswered. JACC Clin Electrophysiol 6:1377–1380. https://doi.org/10.1016/j.jacep.2020.06.034

    Article  PubMed  PubMed Central  Google Scholar 

  3. Huizar JF, Fisher SG, Ramsey FV, Kaszala K, Tan AY, Moore H, Koneru JN, Kron J, Padala SK, Ellenbogen KA, Singh SN (2021) Outcomes of premature ventricular contraction-cardiomyopathy in the veteran population: a secondary analysis of the CHF-STAT study. JACC Clin Electrophysiol 7:380–390. https://doi.org/10.1016/j.jacep.2020.08.028

    Article  PubMed  Google Scholar 

  4. Akkaya M, Roukoz H, Adabag S, Benditt DG, Anand I, Li JM, Zakharova M, Tholakanahalli V (2013) Improvement of left ventricular diastolic function and left atrial reverse remodeling after catheter ablation of premature ventricular complexes. J Interv Card Electrophysiol 38:179–185. https://doi.org/10.1007/s10840-013-9836-0

    Article  PubMed  Google Scholar 

  5. Yokokawa M, Good E, Crawford T, Chugh A, Pelosi F Jr, Latchamsetty R, Jongnarangsin K, Armstrong W, Ghanbari H, Oral H, Morady F, Bogun F (2013) Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm 10:172–175. https://doi.org/10.1016/j.hrthm.2012.10.011

    Article  PubMed  Google Scholar 

  6. Huizar JF, Tan AY, Kaszala K, Ellenbogen KA (2021) Clinical and translational insights on premature ventricular contractions and PVC-induced cardiomyopathy. Prog Cardiovasc Dis 66:17–27. https://doi.org/10.1016/j.pcad.2021.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC, Francis GS, Lenihan D, Lewis EF, McNamara DM, Pahl E, Vasan RS, Ramasubbu K, Rasmusson K, Towbin JA, Yancy C, American Heart Association Committee on Heart F, Transplantation of the Council on Clinical C, Council on Cardiovascular Disease in the Y, Council on C, Stroke N, Council on E, Prevention, Council on Quality of C and Outcomes R (2016) Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the american heart association. Circulation 134:e579–e646. https://doi.org/10.1161/CIR.0000000000000455

    Article  PubMed  Google Scholar 

  8. Huizar JF, Kaszala K, Potfay J, Minisi AJ, Lesnefsky EJ, Abbate A, Mezzaroma E, Chen Q, Kukreja RC, Hoke NN, Thacker LR 2nd, Ellenbogen KA, Wood MA (2011) Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol 4:543–549. https://doi.org/10.1161/CIRCEP.111.962381

    Article  PubMed  PubMed Central  Google Scholar 

  9. Walters TE, Rahmutula D, Szilagyi J, Alhede C, Sievers R, Fang Q, Olgin J, Gerstenfeld EP (2018) Left ventricular dyssynchrony predicts the cardiomyopathy associated with premature ventricular contractions. J Am Coll Cardiol 72:2870–2882. https://doi.org/10.1016/j.jacc.2018.09.059

    Article  PubMed  Google Scholar 

  10. Yamada S, Lo LW, Chou YH, Lin WL, Chang SL, Lin YJ, Liu SH, Cheng WH, Tsai TY, Chen SA (2017) Beneficial effect of renal denervation on ventricular premature complex induced cardiomyopathy. J Am Heart Assoc. https://doi.org/10.1161/JAHA.116.004479

    Article  PubMed  PubMed Central  Google Scholar 

  11. Torrado J, Kowlgi GN, Ramirez RJ, Balderas-Villalobos J, Jovin D, Parker C, Om E, Airapetov S, Kaszala K, Tan AY, Ellenbogen KA, Huizar JF (2021) Eccentric hypertrophy in an animal model of mid- and long-term premature ventricular contraction-induced cardiomyopathy. Heart Rhythm O2(2):80–88. https://doi.org/10.1016/j.hroo.2020.12.021

    Article  Google Scholar 

  12. Wang Y, Eltit JM, Kaszala K, Tan A, Jiang M, Zhang M, Tseng GN, Huizar JF (2014) Cellular mechanism of premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 11:2064–2072. https://doi.org/10.1016/j.hrthm.2014.07.022

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tada M, Yamada M, Kadoma M, Inui M, Ohmori F (1982) Calcium transport by cardiac sarcoplasmic reticulum and phosphorylation of phospholamban. Mol Cell Biochem 46:73–95. https://doi.org/10.1007/BF00236776

    Article  PubMed  Google Scholar 

  14. Bers DM (2000) Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 87:275–281. https://doi.org/10.1161/01.res.87.4.275

    Article  CAS  PubMed  Google Scholar 

  15. Li L, Desantiago J, Chu G, Kranias EG, Bers DM (2000) Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol 278:H769–H779. https://doi.org/10.1152/ajpheart.2000.278.3.H769

    Article  CAS  PubMed  Google Scholar 

  16. Berlin JR, Bassani JW, Bers DM (1994) Intrinsic cytosolic calcium buffering properties of single rat cardiac myocytes. Biophys J 67:1775–1787. https://doi.org/10.1016/S0006-3495(94)80652-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bassani RA, Shannon TR, Bers DM (1998) Passive Ca2+ binding in ventricular myocardium of neonatal and adult rats. Cell Calcium 23:433–442. https://doi.org/10.1016/s0143-4160(98)90100-2

    Article  CAS  PubMed  Google Scholar 

  18. Penny WF, Hammond HK (2017) Randomized clinical trials of gene transfer for heart failure with reduced ejection fraction. Hum Gene Ther 28:378–384. https://doi.org/10.1089/hum.2016.166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Belevych A, Kubalova Z, Terentyev D, Hamlin RL, Carnes CA, Gyorke S (2007) Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure. Biophys J 93:4083–4092. https://doi.org/10.1529/biophysj.107.114546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ruchala I, Cabra V, Solis E Jr, Glennon RA, De Felice LJ, Eltit JM (2014) Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels. Cell Calcium 56:25–33. https://doi.org/10.1016/j.ceca.2014.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kubalova Z, Gyorke I, Terentyeva R, Viatchenko-Karpinski S, Terentyev D, Williams SC, Gyorke S (2004) Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes. J Physiol 561:515–524. https://doi.org/10.1113/jphysiol.2004.073940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shannon TR, Guo T, Bers DM (2003) Ca2+ scraps: local depletions of free [Ca2+] in cardiac sarcoplasmic reticulum during contractions leave substantial Ca2+ reserve. Circ Res 93:40–45. https://doi.org/10.1161/01.RES.0000079967.11815.19

    Article  CAS  PubMed  Google Scholar 

  23. Guo T, Ai X, Shannon TR, Pogwizd SM, Bers DM (2007) Intra-sarcoplasmic reticulum free [Ca2+] and buffering in arrhythmogenic failing rabbit heart. Circ Res 101:802–810. https://doi.org/10.1161/CIRCRESAHA.107.152140

    Article  CAS  PubMed  Google Scholar 

  24. Puglisi JL, Bers DM (2001) LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport. Am J Physiol Cell Physiol 281:C2049–C2060. https://doi.org/10.1152/ajpcell.2001.281.6.C2049

    Article  CAS  PubMed  Google Scholar 

  25. Sikkel MB, Francis DP, Howard J, Gordon F, Rowlands C, Peters NS, Lyon AR, Harding SE, MacLeod KT (2017) Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies. Cardiovasc Res 113:1743–1752. https://doi.org/10.1093/cvr/cvx151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Eisner DA (2021) Pseudoreplication in physiology: more means less. J Gen Physiol. https://doi.org/10.1085/jgp.202012826

    Article  PubMed  PubMed Central  Google Scholar 

  27. Frank KF, Bolck B, Brixius K, Kranias EG, Schwinger RH (2002) Modulation of SERCA: implications for the failing human heart. Basic Res Cardiol 97(Suppl 1):I72–I78. https://doi.org/10.1007/s003950200033

    Article  PubMed  Google Scholar 

  28. Bovo E, Nikolaienko R, Bhayani S, Kahn D, Cao Q, Martin JL, Kuo IY, Robia SL, Zima AV (2019) Novel approach for quantification of endoplasmic reticulum Ca(2+) transport. Am J Physiol Heart Circ Physiol 316:H1323–H1331. https://doi.org/10.1152/ajpheart.00031.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kentish JC, McCloskey DT, Layland J, Palmer S, Leiden JM, Martin AF, Solaro RJ (2001) Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res 88:1059–1065. https://doi.org/10.1161/hh1001.091640

    Article  CAS  PubMed  Google Scholar 

  30. 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. https://doi.org/10.1113/jphysiol.2004.061176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang M, Zhang M, Howren M, Wang Y, Tan A, Balijepalli RC, Huizar JF, Tseng GN (2016) JPH-2 interacts with Cai-handling proteins and ion channels in dyads: contribution to premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 13:743–752. https://doi.org/10.1016/j.hrthm.2015.10.037

    Article  CAS  PubMed  Google Scholar 

  32. Nediani C, Formigli L, Perna AM, Pacini A, Ponziani V, Modesti PA, Ibba-Manneschi L, Zecchi-Orlandini S, Fiorillo C, Cecchi C, Liguori P, Fratini G, Vanni S, Nassi P (2002) Biochemical changes and their relationship with morphological and functional findings in pig heart subjected to lasting volume overload: a possible role of acylphosphatase in the regulation of sarcoplasmic reticulum calcium pump. Basic Res Cardiol 97:469–478. https://doi.org/10.1007/s00395-002-0367-6

    Article  CAS  PubMed  Google Scholar 

  33. Simmerman HK, Jones LR (1998) Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev 78:921–947. https://doi.org/10.1152/physrev.1998.78.4.921

    Article  CAS  PubMed  Google Scholar 

  34. Nediani C, Celli A, Fiorillo C, Ponziani V, Giannini L, Nassi P (2003) Acylphosphatase interferes with SERCA2a-PLN association. Biochem Biophys Res Commun 301:948–951. https://doi.org/10.1016/s0006-291x(03)00078-0

    Article  CAS  PubMed  Google Scholar 

  35. Koss KL, Kranias EG (1996) Phospholamban: a prominent regulator of myocardial contractility. Circ Res 79:1059–1063. https://doi.org/10.1161/01.res.79.6.1059

    Article  CAS  PubMed  Google Scholar 

  36. Tan AY, Elharrif K, Cardona-Guarache R, Mankad P, Ayers O, Joslyn M, Das A, Kaszala K, Lin SF, Ellenbogen KA, Minisi AJ, Huizar JF (2020) Persistent proarrhythmic neural remodeling despite recovery from premature ventricular contraction-induced cardiomyopathy. J Am Coll Cardiol 75:1–13. https://doi.org/10.1016/j.jacc.2019.10.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Salavatian S, Yamaguchi N, Hoang J, Lin N, Patel S, Ardell JL, Armour JA, Vaseghi M (2019) Premature ventricular contractions activate vagal afferents and alter autonomic tone: implications for premature ventricular contraction-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 317:H607–H616. https://doi.org/10.1152/ajpheart.00286.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was partially funded by National Institutes of Health grant R01 HL139874 (J.H.) and R01 AR068431 (M.S.), Department of Veterans Affairs grant 5I01BX004861 (J.H.), and a postdoctoral fellowship from the American Heart Association and the D.C. Women’s Board 836430 (J.B.V.).

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, 1101 E Marshall St, 3-038H, Richmond, VA, 23298, USA

    Jaime Balderas-Villalobos, J. M. L. Medina-Contreras, Christopher Lynch, Rafael J. Ramirez, Montserrat Samsó & Jose M. Eltit

  2. Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA

    Rajiv Kabadi, Alex Y. Tan, Karoly Kaszala & Jose F. Huizar

  3. Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, USA

    Alex Y. Tan, Karoly Kaszala & Jose F. Huizar

Authors
  1. Jaime Balderas-Villalobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. M. L. Medina-Contreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rajiv Kabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rafael J. Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alex Y. Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karoly Kaszala
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Montserrat Samsó
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jose F. Huizar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jose M. Eltit
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JE and JH: conceived and supervised the study. JE, JH, JB, and MS: designed the experiments. JB, JE, JH, JM, CL, RK, RR, AT, KK, and MS: performed experiments. JB, JE, RK, and JH: analyzed the data. JE: wrote the manuscript. JB, JH, and MS: made manuscript revisions.

Corresponding author

Correspondence to Jose M. Eltit.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Balderas-Villalobos, J., Medina-Contreras, J.M.L., Lynch, C. et al. Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy. Mol Cell Biochem 478, 1447–1456 (2023). https://doi.org/10.1007/s11010-022-04605-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04605-y

Keywords

Search

Navigation