Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2011

Open Access 01-12-2011 | Research

SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice

Authors: Jin-Hong Shin, Brian Bostick, Yongping Yue, Roger Hajjar, Dongsheng Duan

Published in: Journal of Translational Medicine | Issue 1/2011

Login to get access

Abstract

Background

Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD) heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG) abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy.

Methods

1 × 1012 viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9) SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5) via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later.

Results

The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities.

Conclusions

Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.
Appendix
Available only for authorised users
Literature
1.
Shin J-H, Bostick B, Yue Y, Duan D: Duchenne cardiomyopathy gene therapy. Muscle gene therapy. Edited by: Duan D. 2010, New York: Springer Science + Business Media, LLC, 141-162.CrossRef
2.
Dunn JF, Radda GK: Total ion content of skeletal and cardiac muscle in the mdx mouse dystrophy: Ca2+ is elevated at all ages. J Neurol Sci. 1991, 103: 226-231. 10.1016/0022-510X(91)90168-7.CrossRefPubMed
3.
Alloatti G, Gallo MP, Penna C, Levi RC: Properties of cardiac cells from dystrophic mouse. J Mol Cell Cardiol. 1995, 27: 1775-1779. 10.1016/S0022-2828(95)91019-0.CrossRefPubMed
4.
Williams IA, Allen DG: Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol. 2007, 292: H846-855.CrossRefPubMed
5.
Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR, Lacampagne A: Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. Proc Natl Acad Sci USA. 2010, 107: 1559-1564. 10.1073/pnas.0908540107.PubMedCentralCrossRefPubMed
6.
Sarma S, Li N, van Oort RJ, Reynolds C, Skapura DG, Wehrens XH: Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy. Proc Natl Acad Sci USA. 2010, 107: 13165-13170. 10.1073/pnas.1004509107.PubMedCentralCrossRefPubMed
7.
Frank KF, Bolck B, Erdmann E, Schwinger RH: Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation. Cardiovasc Res. 2003, 57: 20-27. 10.1016/S0008-6363(02)00694-6.CrossRefPubMed
8.
Kawase Y, Hajjar RJ: The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med. 2008, 5: 554-565. 10.1038/ncpcardio1301.CrossRefPubMed
9.
Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ: Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther. 2010, 10: 29-41. 10.1517/14712590903321462.PubMedCentralCrossRefPubMed
10.
Rohman MS, Emoto N, Takeshima Y, Yokoyama M, Matsuo M: Decreased mAKAP, ryanodine receptor, and SERCA2a gene expression in mdx hearts. Biochem Biophys Res Commun. 2003, 310: 228-235. 10.1016/j.bbrc.2003.09.005.CrossRefPubMed
11.
Ghosh A, Yue Y, Shin J-H, Duan D: Systemic trans-splicing AAV delivery efficiently transduces the heart of adult mdx mouse, a model for Duchenne muscular dystrophy. Hum Gene Ther. 2009, 20: 1319-1328. 10.1089/hum.2009.058.PubMedCentralCrossRefPubMed
12.
Bostick B, Yue Y, Lai Y, Long C, Li D, Duan D: Adeno-associated virus serotype-9 microdystrophin gene therapy ameliorates electrocardiographic abnormalities in mdx mice. Hum Gene Ther. 2008, 19: 851-856. 10.1089/hum.2008.058.PubMedCentralCrossRefPubMed
13.
Bostick B, Shin J-H, Yue Y, Duan D: AAV-microdystrophin therapy improves cardiac performance in aged female mdx mice. Mol Ther. 2011, online publication on August 2 2011. doi:10.1038/mt.2011.154,
14.
Bostick B, Yue Y, Duan D: Gender influences cardiac function in the mdx model of Duchenne cardiomyopathy. Muscle Nerve. 2010, 42: 600-603. 10.1002/mus.21763.PubMedCentralCrossRefPubMed
15.
Bostick B, Yue Y, Long C, Duan D: Prevention of Dystrophin-Deficient Cardiomyopathy in Twenty-One-Month-Old Carrier Mice by Mosaic Dystrophin Expression or Complementary Dystrophin/Utrophin Expression. Circ Res. 2008, 102: 121-130. 10.1161/CIRCRESAHA.107.162982.CrossRefPubMed
16.
Sakata S, Lebeche D, Sakata N, Sakata Y, Chemaly ER, Liang LF, Tsuji T, Takewa Y, del Monte F, Peluso R, Zsebo K, Jeong D, Park WJ, Kawase Y, Hajjar RJ: Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol. 2007, 42: 852-861. 10.1016/j.yjmcc.2007.01.003.PubMedCentralCrossRefPubMed
17.
Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, Hadri L, Yoneyama R, Hoshino K, Takewa Y, Sakata S, Peluso R, Zsebo K, Gwathmey JK, Tardif JC, Tanguay JF, Hajjar RJ: 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: 1112-1119. 10.1016/j.jacc.2007.12.014.CrossRefPubMed
18.
Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M: Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail. 2008, 14: 355-367. 10.1016/j.cardfail.2008.02.005.CrossRefPubMed
19.
Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ: Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail. 2009, 15: 171-181. 10.1016/j.cardfail.2009.01.013.PubMedCentralCrossRefPubMed
20.
Ghosh A, Yue Y, Long C, Bostick B, Duan D: Efficient whole-body transduction with trans-splicing adeno-associated viral vectors. Mol Ther. 2007, 15: 750-755.PubMedCentralCrossRefPubMed
21.
Bostick B, Ghosh A, Yue Y, Long C, Duan D: Systemic AAV-9 transduction in mice is influenced by animal age but not by the route of administration. Gene Ther. 2007, 14: 1605-1609. 10.1038/sj.gt.3303029.CrossRefPubMed
22.
Lai Y, Yue Y, Liu M, Ghosh A, Engelhardt JF, Chamberlain JS, Duan D: Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors. Nat Biotechnol. 2005, 23: 1435-1439. 10.1038/nbt1153.PubMedCentralCrossRefPubMed
23.
Xu Z, Yue Y, Lai Y, Ye C, Qiu J, Pintel DJ, Duan D: Trans-splicing adeno-associated viral vector-mediated gene therapy is limited by the accumulation of spliced mRNA but not by dual vector coinfection efficiency. Hum Gene Ther. 2004, 15: 896-905.PubMedCentralCrossRefPubMed
24.
Duan D, Yue Y, Zhou W, Labed B, Ritche TC, Grosschedl R, Engelhardt JF: Submucosal Gland Development in the Airway is Controlled by Lymphoid Enhancer Binding Factor-1 (Lef-1). Development. 1999, 126: 4441-4453.PubMed
25.
Bostick B, Yue Y, Long C, Marschalk N, Fine DM, Chen J, Duan D: Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice. Mol Ther. 2009, 17: 253-261. 10.1038/mt.2008.264.PubMedCentralCrossRefPubMed
26.
Hadri L, Bobe R, Kawase Y, Ladage D, Ishikawa K, Atassi F, Lebeche D, Kranias EG, Leopold JA, Lompre AM, Lompré AM, Lipskaia L, Hajjar RJ: SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells. Mol Ther. 2010, 18: 1284-1292. 10.1038/mt.2010.77.PubMedCentralCrossRefPubMed
27.
Yue Y, Liu M, Duan D: C-terminal truncated microdystrophin recruits dystrobrevin and syntrophin to the dystrophin-associated glycoprotein complex and reduces muscular dystrophy in symptomatic utrophin/dystrophin double knock-out mice. Mol Ther. 2006, 14: 79-87. 10.1016/j.ymthe.2006.01.007.PubMedCentralCrossRefPubMed
28.
29.
30.
Beeri R, Chaput M, Guerrero JL, Kawase Y, Yosefy C, Abedat S, Karakikes I, Morel C, Tisosky A, Sullivan S, Handschumacher MD, Gilon D, Vlahakes GJ, Hajjar RJ, Levine RA: Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricular remodeling in ischemic mitral regurgitation. Circ Heart Fail. 2010, 3: 627-634. 10.1161/CIRCHEARTFAILURE.109.891184.PubMedCentralCrossRefPubMed
31.
Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ: Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure. Circulation. 2011, 124: 304-313. 10.1161/CIRCULATIONAHA.111.022889.CrossRefPubMed
32.
Divet A, Lompre AM, Huchet-Cadiou C: Effect of cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum Ca-ATPase, on skeletal muscles from normal and mdx mice. Acta Physiol Scand. 2005, 184: 173-186. 10.1111/j.1365-201X.2005.01450.x.CrossRefPubMed
33.
Kaspar RW, Allen HD, Montanaro F: Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract. 2009, 21: 241-249. 10.1111/j.1745-7599.2009.00404.x.PubMedCentralCrossRefPubMed
34.
Yue Y, Li Z, Harper SQ, Davisson RL, Chamberlain JS, Duan D: Microdystrophin Gene Therapy of Cardiomyopathy Restores Dystrophin-Glycoprotein Complex and Improves Sarcolemma Integrity in the Mdx Mouse Heart. Circulation. 2003, 108: 1626-1632. 10.1161/01.CIR.0000089371.11664.27.PubMedCentralCrossRefPubMed
35.
Townsend D, Blankinship MJ, Allen JM, Gregorevic P, Chamberlain JS, Metzger JM: Systemic Administration of Micro-dystrophin Restores Cardiac Geometry and Prevents Dobutamine-induced Cardiac Pump Failure. Mol Ther. 2007, 15: 1086-1092.PubMed
36.
Wu B, Moulton HM, Iversen PL, Jiang J, Li J, Spurney CF, Sali A, Guerron AD, Nagaraju K, Doran T, Lu P, Xiao X, Lu QL: Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc Natl Acad Sci USA. 2008, 105: 14814-14819. 10.1073/pnas.0805676105.PubMedCentralCrossRefPubMed
37.
Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S, Bowles D, Gray S, Li C, Galloway G, Malik V, Coley B, Clark KR, Li J, Xiao X, Samulski J, McPhee SW, Samulski RJ, Walker CM: Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med. 2010, 363: 1429-1437. 10.1056/NEJMoa1000228.PubMedCentralCrossRefPubMed
38.
Constantin B, Sebille S, Cognard C: New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD. J Muscle Res Cell Motil. 2006, 27: 375-386. 10.1007/s10974-006-9085-2.CrossRefPubMed
39.
Allen DG, Gervasio OL, Yeung EW, Whitehead NP: Calcium and the damage pathways in muscular dystrophy. Can J Physiol Pharmacol. 2010, 88: 83-91. 10.1139/Y09-058.CrossRefPubMed
40.
Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, Metzger JM: Dystrophic heart failure blocked by membrane sealant poloxamer. Nature. 2005, 436: 1025-1029. 10.1038/nature03844.CrossRefPubMed
41.
Fanchaouy M, Polakova E, Jung C, Ogrodnik J, Shirokova N, Niggli E: Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes. Cell Calcium. 2009, 46: 114-121. 10.1016/j.ceca.2009.06.002.PubMedCentralCrossRefPubMed
42.
Janssen PM, Hiranandani N, Mays TA, Rafael-Fortney JA: Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice. Am J Physiol Heart Circ Physiol. 2005, 289: H2373-2378. 10.1152/ajpheart.00448.2005.CrossRefPubMed
43.
Goonasekera SA, Lam CK, Millay DP, Sargent MA, Hajjar RJ, Kranias EG, Molkentin JD: Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. J Clin Invest. 2011, 121: 1044-1052. 10.1172/JCI43844.PubMedCentralCrossRefPubMed
Metadata
Title
SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice
Authors
Jin-Hong Shin
Brian Bostick
Yongping Yue
Roger Hajjar
Dongsheng Duan
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2011
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-9-132

Other articles of this Issue 1/2011

Journal of Translational Medicine 1/2011 Go to the issue

Research

Liver-spleen axis, insulin-like growth factor-(IGF)-I axis and fat mass in overweight/obese females

Research

Promoter methylation and downregulation of SLC22A18 are associated with the development and progression of human glioma

Research

Protein kinase CK2α is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes

Protocol

Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I)

Research

Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remission

Research

Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits