Abstract

Heart failure is characterized by a number of abnormalities at the cellular level in the various steps of excitation-contraction coupling. One of the key abnormalities in both human and experimental heart failure is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handling. Deficient SR Ca2+ uptake during relaxation has been identified in hypertrophied and failing hearts from both human and animal models and has been associated with a decrease in the expression and activity of SR Ca2+-ATPase. Recently, adenovirus vectors have been shown to be efficient in transferring exogenous genes into myocardial cells. Using replication-deficient recombinant adenoviral vectors, the applicant plans to introduce the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene directly into rats with pressure-overload induced heart failure which are known to have a decrease in SERCA2a expression. The applicant will validate the use of adenoviral gene transfer in the rat model of heart failure and will test the hypothesis that increasing the expression of SERCA2a will restore contractility and normalize intracellular calcium cycling in this model of heart failure.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057263-03
Application #
2883289
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1997-02-10
Project End
2001-01-31
Budget Start
1999-02-10
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Hadri, Lahouaria; Kratlian, Razmig G; Benard, Ludovic et al. (2013) Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension. Circulation 128:512-23
Lompré, A-M; Hadri, L; Merlet, E et al. (2013) Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy. Gene Ther 20:901-12
Lipskaia, L; Hadri, L; Le Prince, P et al. (2013) SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery. Gene Ther 20:396-406
Hadri, Lahouaria; Bobe, Regis; Kawase, Yoshiaki et al. (2010) SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells. Mol Ther 18:1284-92
Lipskaia, Larissa; Chemaly, Elie R; Hadri, Lahouaria et al. (2010) Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther 10:29-41
Ly, Hung Q; Hoshino, Kozo; Pomerantseva, Irina et al. (2009) In vivo myocardial distribution of multipotent progenitor cells following intracoronary delivery in a swine model of myocardial infarction. Eur Heart J 30:2861-8
Sakata, Susumu; Lebeche, Djamel; Sakata, Naoya et al. (2007) Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol 42:852-61