Modulation of ventricular function through gene transfer in vivo.
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.
Hajjar
R J
RJ
Cardiovascular Research Center and Heart Failure and Cardiac Transplantation Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Schmidt
U
U
Matsui
T
T
Guerrero
J L
JL
Lee
K H
KH
Gwathmey
J K
JK
Dec
G W
GW
Semigran
M J
MJ
Rosenzweig
A
A
D000260:Adenoviruses, Human; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D002404:Catheterization; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006321:Heart / Q000502:physiology*; D006439:Hemodynamics; D007545:Isoproterenol / Q000494:pharmacology; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D014161:Transduction, Genetic; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D000099211:Phospholamban