Sarcoplasmic Reticulum Ca(2+) ATPase As a Therapeutic Target for Heart Failure

Overview

Journal Expert Opin Biol Ther

Specialties Biology
Pharmacology

Date 2010 Jan 19

PMID 20078230

Citations 93

Authors

Larissa Lipskaia

Elie R Chemaly

Lahouaria Hadri

Anne-Marie Lompre

Roger J Hajjar

Affiliations

Soon will be listed here.

Abstract

The cardiac isoform of the sarco/endoplasmic reticulum Ca(2+)ATPase (SERCA2a) plays a major role in controlling excitation/contraction coupling. In both experimental and clinical heart failure, SERCA2a expression is significantly reduced which leads to abnormal Ca(2+) handling and deficient contractility. A large number of studies in isolated cardiac myocytes and in small and large animal models of heart failure showed that restoring SERCA2a expression by gene transfer corrects the contractile abnormalities and improves energetics and electrical remodeling. Following a long line of investigation, a clinical trial is underway to restore SERCA2a expression in patients with heart failure using adeno-associated virus type 1. This review addresses the following issues regarding heart failure gene therapy: i) new insights on calcium regulation by SERCA2a; ii) SERCA2a as a gene therapy target in animal models of heart failure; iii) advances in the development of viral vectors and gene delivery; and iv) clinical trials on heart failure using SERCA2a. This review focuses on the new advances in SERCA2a- targeted gene therapy made in the last three years. In conclusion, SERCA2a is an important therapeutic target in various cardiovascular disorders. Ongoing clinical gene therapy trials will provide answers on its safety and applicability.

Citing Articles

Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM.

Ryu G, Ko M, Lee S, Park S, Choi J, Lee J Biomolecules. 2025; 14(12.

PMID: 39766212 PMC: 11673756. DOI: 10.3390/biom14121505.

Interpreting Diastolic Dynamics and Evaluation through Echocardiography.

Zhang X, Li K, Cardoso C, Moctezuma-Ramirez A, Elgalad A Life (Basel). 2024; 14(9).

PMID: 39337939 PMC: 11433582. DOI: 10.3390/life14091156.

Application of Calcium Kinetics Characterization in Cardiac Disease Modeling and Drug Discovery.

Roberts R, Lam C Biomolecules. 2024; 14(7).

PMID: 39062578 PMC: 11274611. DOI: 10.3390/biom14070865.

Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.

Agyapong E, Pedriali G, Ramaccini D, Bouhamida E, Tremoli E, Giorgi C J Transl Med. 2024; 22(1):552.

PMID: 38853272 PMC: 11162575. DOI: 10.1186/s12967-024-05240-5.

Single Nucleotide Polymorphisms in Coronary Microvascular Dysfunction.

Stein A, Harder J, Holmes H, Merz C, Pepine C, Keeley E J Am Heart Assoc. 2024; 13(4):e032137.

PMID: 38348798 PMC: 11010085. DOI: 10.1161/JAHA.123.032137.

References

Choi V, Samulski R, McCarty D . Effects of adeno-associated virus DNA hairpin structure on recombination. J Virol. 2005; 79(11):6801-7. PMC: 1112146. DOI: 10.1128/JVI.79.11.6801-6807.2005. View

Lipskaia L, Monte F, Capiod T, Yacoubi S, Hadri L, Hours M . Sarco/endoplasmic reticulum Ca2+-ATPase gene transfer reduces vascular smooth muscle cell proliferation and neointima formation in the rat. Circ Res. 2005; 97(5):488-95. DOI: 10.1161/01.RES.0000180663.42594.aa. View

Venetucci L, Trafford A, ONeill S, Eisner D . The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res. 2007; 77(2):285-92. DOI: 10.1093/cvr/cvm009. View

Vangheluwe P, Tjwa M, Van den Bergh A, Louch W, Beullens M, Dode L . A SERCA2 pump with an increased Ca2+ affinity can lead to severe cardiac hypertrophy, stress intolerance and reduced life span. J Mol Cell Cardiol. 2006; 41(2):308-17. DOI: 10.1016/j.yjmcc.2006.05.014. View

ODonnell J, Fields A, Xu X, Chowdhury S, Geenen D, Bi J . Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. Am J Physiol Heart Circ Physiol. 2008; 295(6):H2483-94. PMC: 2614552. DOI: 10.1152/ajpheart.01023.2008. View

Lipskaia L, Ly H, Kawase Y, Hajjar R, Lompre A . Treatment of heart failure by calcium cycling gene therapy. Future Cardiol. 2009; 3(4):413-23. DOI: 10.2217/14796678.3.4.413. View

Liu Q, Wilkins B, Lee Y, Ichijo H, Molkentin J . Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth. Mol Cell Biol. 2006; 26(10):3785-97. PMC: 1489013. DOI: 10.1128/MCB.26.10.3785-3797.2006. View

Micheletti R, Palazzo F, Barassi P, Giacalone G, Ferrandi M, Schiavone A . Istaroxime, a stimulator of sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure. Am J Cardiol. 2007; 99(2A):24A-32A. DOI: 10.1016/j.amjcard.2006.09.003. View

Prunier F, Kawase Y, Gianni D, Scapin C, Danik S, Ellinor P . Prevention of ventricular arrhythmias with sarcoplasmic reticulum Ca2+ ATPase pump overexpression in a porcine model of ischemia reperfusion. Circulation. 2008; 118(6):614-24. DOI: 10.1161/CIRCULATIONAHA.108.770883. View

10.

Koerber J, Jang J, Schaffer D . DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther. 2008; 16(10):1703-9. PMC: 2683895. DOI: 10.1038/mt.2008.167. View

11.

Schmitt J, Kamisago M, Asahi M, Li G, Ahmad F, Mende U . Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003; 299(5611):1410-3. DOI: 10.1126/science.1081578. View

12.

Kawase Y, Ly H, Prunier F, Lebeche D, Shi Y, Jin H . Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol. 2008; 51(11):1112-9. DOI: 10.1016/j.jacc.2007.12.014. View

13.

Pacak C, Mah C, Thattaliyath B, Conlon T, Lewis M, Cloutier D . Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res. 2006; 99(4):e3-9. DOI: 10.1161/01.RES.0000237661.18885.f6. View

14.

Most P, Pleger S, Volkers M, Heidt B, Boerries M, Weichenhan D . Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. J Clin Invest. 2004; 114(11):1550-63. PMC: 529280. DOI: 10.1172/JCI21454. View

15.

McCarty D, Fu H, Monahan P, Toulson C, Naik P, Samulski R . Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 2003; 10(26):2112-8. DOI: 10.1038/sj.gt.3302134. View

16.

Gray S, Samulski R . Optimizing gene delivery vectors for the treatment of heart disease. Expert Opin Biol Ther. 2008; 8(7):911-22. DOI: 10.1517/14712598.8.7.911. View

17.

Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N . Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007; 117(4):e25-146. DOI: 10.1161/CIRCULATIONAHA.107.187998. View

18.

Monte F, Hajjar R . Intracellular devastation in heart failure. Heart Fail Rev. 2008; 13(2):151-62. DOI: 10.1007/s10741-007-9071-9. View

19.

del MonteF , Harding S, Schmidt U, Matsui T, Kang Z, Dec G . Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 1999; 100(23):2308-11. PMC: 1249502. DOI: 10.1161/01.cir.100.23.2308. View

20.

Suckau L, Fechner H, Chemaly E, Krohn S, Hadri L, Kockskamper J . Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation. 2009; 119(9):1241-52. PMC: 4298485. DOI: 10.1161/CIRCULATIONAHA.108.783852. View