Restoration of Contractile Function in Isolated Cardiomyocytes From Failing Human Hearts by Gene Transfer of SERCA2a
Open accessAbstract
Background —Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca 2+ uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca 2+ ATPase (SERCA2a) pump. Methods and Results —To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca 2+ handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7±6.7% versus 16.6±2.7% shortening per second, P <0.005) and enhanced relaxation velocity (32.0±10.1% versus 15.1±2.4%, P <0.005). Diastolic Ca 2+ was decreased in failing cardiomyocytes overexpressing SERCA2a (270±26 versus 347±30 nmol/L, P <0.005), whereas systolic Ca 2+ was increased (601±38 versus 508±25 nmol/L, P <0.05). In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a. Conclusions —These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the treatment of this disease.
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- Authors
- del Monte, F., Harding, S. E., Schmidt, U., Matsui, T., Kang, Z. B., Dec, G. W., Gwathmey, J. K., Rosenzweig, A., & Hajjar, R. J.
- Affiliations
- Boston University (US)
- From the Cardiovascular Research Center (F.d.M., U.S., T.M., Z.B.K., A.R.) and the Heart Failure and Cardiac Transplantation Center (G.W.D., R.J.H.), Massachusetts General Hospital, Harvard Medical School, and Boston University School of Medicine (J.K.G.), Boston, Mass; and Imperial College, London, UK (S.E.H.).
- Venue
- Circulation
- Published
- 1999-12-07
- Volume
- 100
- Issue
- 23
- Pages
- 2308-2311
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC1249502
- OpenAlex
- W2157581901
- Cited by
- 502
- References
- 20
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 6 · 2023: 5 · 2022: 13 · 2021: 16 · 2020: 10 · 2019: 11 · 2018: 15 · 2017: 17 · 2016: 18 · 2015: 17 · 2014: 12 · 2013: 28 · 2012: 30
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- Massachusetts General Hospital
- British Heart Foundation
- National Institutes of Health (5r44hl060323-03, 5r01hl049574-07)
- National Heart, Lung, and Blood Institute (R01 HL049574-05, HL-57623, HL 50361, R01 HL049574-05S1, HL 54202, R44 HL060323-03, R44 HL060323-02A1, R01 HL049574-06S1, R01 HL049574-06, R01 HL049574-08, R01 HL049574-07, R01HL059521)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac pacing and defibrillation studies
- Keywords
- SERCA2a, sarcoplasmic reticulum Ca2+-ATPase, heart failure, cardiomyocytes, gene transfer, contractile function, calcium handling, diastolic calcium, relaxation velocity, contraction velocity, frequency response, gene therapy
- MeSH terms
- Calcium-Transporting ATPases, Calcium, Cardiomyopathy, Dilated, Cells, Cultured, Heart Failure, Humans, Myocardial Contraction, Sarcoplasmic Reticulum, Genetic Therapy, Gene Expression, Muscle Fibers, Skeletal
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