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PMID: 9560262 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Modulation of ventricular function through gene transfer in vivo.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 9 ·1998-04-28 ·Pages 5251-6

Hajjar RJ, Schmidt U, Matsui T, Guerrero JL, Lee KH, Gwathmey JK, Dec GW, Semigran MJ, Rosenzweig A

Abstract

We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase (beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.betagal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 +/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6) or hearts infected with Ad.betagal (92.6 +/- 5.9 mmHg, n = 6). Both peak rate of pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s, n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts (+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with Ad.betagal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5 +/- 1.0 ms, n = 6) or hearts infected with Ad.betagal (20.8 +/- 2.1 ms, n = 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.

MeSH Terms
Adenoviruses, Human Animals Calcium-Binding Proteins/genetics Catheterization Gene Expression Gene Transfer Techniques Genetic Vectors Heart/physiology Hemodynamics Isoproterenol/pharmacology Rats Sarcoplasmic Reticulum/physiology Transduction, Genetic
Chemicals
Calcium-Binding Proteins phospholamban Isoproterenol
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Hajjar R J
Cardiovascular Research Center and Heart Failure and Cardiac Transplantation Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Schmidt U
Matsui T
Guerrero J L
Lee K H
Gwathmey J K
Dec G W
Semigran M J
Rosenzweig A
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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.95.9.5251
Published
1998-04-28
Pages
5251-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC20247
Subset
IM
Grants
NHLBI NIH HHS · R01 HL059521 · United States
NHLBI NIH HHS · HL 50361 · United States
NHLBI NIH HHS · HL 54202 · United States
NHLBI NIH HHS · HL 57623 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.9.5251 PMC Full Text View journal details
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