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PMID: 10639159 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 2 ·2000-01-18 ·Pages 793-8

Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, Hajjar RJ

Abstract

In human and experimental models of heart failure, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances in calcium metabolism have been shown to contribute significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constriction in rats. After 19-23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25% decrease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosidase (Ad.betagal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad. betagal were characterized by a significant decrease in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n = 11). In addition, these failing hearts had reduced left-ventricular systolic pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt, -dP/dt), and rate of isovolumic relaxation (tau). Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to nonfailing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in left-ventricular systolic pressure, +dP/dt, -dP/dt, and rate of isovolumic relaxation (tau) normalizing them back to levels comparable to sham-operated rats. In this study, we show that in an animal model of heart failure where SERCA2a protein levels and activity are decreased and severe contractile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels.

MeSH Terms
Adenoviridae/genetics Adrenergic beta-Agonists/pharmacology Animals Aorta/physiology Calcium/metabolism Calcium-Transporting ATPases/genetics,metabolism Constriction Gene Expression Regulation, Enzymologic Gene Transfer Techniques Green Fluorescent Proteins Heart Failure/genetics,physiopathology,therapy Heart Ventricles/pathology Hemodynamics Hypertrophy, Left Ventricular/genetics,physiopathology,therapy Isoproterenol/pharmacology Luminescent Proteins/genetics,metabolism Myocardial Contraction/drug effects Myocardium/cytology,metabolism Rats Rats, Wistar Recombinant Fusion Proteins/genetics,metabolism Sarcoplasmic Reticulum/enzymology Stroke Volume Ventricular Function, Left/physiology beta-Galactosidase/genetics,metabolism
Chemicals
Adrenergic beta-Agonists Luminescent Proteins Recombinant Fusion Proteins Green Fluorescent Proteins beta-Galactosidase Calcium-Transporting ATPases Isoproterenol Calcium
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Miyamoto M I
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
del Monte F
Schmidt U
DiSalvo T S
Kang Z B
Matsui T
Guerrero J L
Gwathmey J K
Rosenzweig A
Hajjar R J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.2.793
Published
2000-01-18
Pages
793-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15410
Subset
IM
Grants
NHLBI NIH HHS · HL 57623 · United States
NHLBI NIH HHS · HL 50361 · United States
NHLBI NIH HHS · R01 HL059521 · United States
NHLBI NIH HHS · R01 HL061557 · United States
NHLBI NIH HHS · HL 54202 · United States
External Links
PubMed source DOI: 10.1073/pnas.97.2.793 PMC Full Text View journal details
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