Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins.
The aim of this study was to examine whether short- and long-term gene transfer of Ca(2+) handling proteins restore left ventricular (LV) mechanoenergetics in aortic banding-induced failing hearts. Aortic-banded rats received recombinant adenoviruses carrying sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) (Banding+SERCA), parvalbumin (Banding+Parv) or beta-galactosidase (Banding+betagal), or an adeno-associated virus carrying SERCA2a (Banding+AAV.SERCA) by a catheter-based technique. LV mechanoenergetic function was measured in cross-circulated hearts. "Banding", "Banding+betagal" and "Banding+saline" groups showed lower end-systolic pressure at 0.1 ml intraballoon water (ESP(0.1)), higher end-diastolic pressure at 0.1 ml intraballoon water (EDP(0.1)) and slower LV relaxation rate, compared with "Normal" and "Sham". However, "Banding+SERCA" and "Banding+Parv" showed high ESP(0.1), low EDP(0.1) and fast LV relaxation rate. In "Banding", "Banding+betagal" and "Banding+saline", slope of relation between cardiac oxygen consumption and systolic pressure-volume area, O(2) cost of total mechanical energy, was twice higher than normal value, whereas slope in "Baning+SERCA" and "Banding+Parv" was similar to normal value. Furthermore, O(2) cost of LV contractility in the 3 control banding groups was approximately 3 times higher than normal value, whereas O(2) cost of contractility in "Banding+SERCA", "Banding+AAV.SERCA" and "Banding+Parv" was as low as normal value. Thus, high O(2) costs of total mechanical energy and of LV contractility in failing hearts indicate energy wasting both in chemomechanical energy transduction and in calcium handling. Improved calcium handling by both short- and long-term overexpression of SERCA2a and parvalbumin transforms the inefficient energy utilization into a more efficient state. Therefore enhancement of calcium handling either by resequestration into the SR or by intracellular buffering improves not only mechanical but energetic function in failing hearts.
Sakata
Susumu
S
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02114, USA.
Lebeche
Djamel
D
Sakata
Naoya
N
Sakata
Yuri
Y
Chemaly
Elie R
ER
Liang
Li Fan
LF
Tsuji
Tsuyoshi
T
Takewa
Yoshiaki
Y
del Monte
Federica
F
Peluso
Richard
R
Zsebo
Krisztina
K
Jeong
Dongtak
D
Park
Woo Jin
WJ
Kawase
Yoshiaki
Y
Hajjar
Roger J
RJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000201:enzymology*; D002118:Calcium; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D008297:Male; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D016277:Ventricular Function, Left; D001616:beta-Galactosidase / Q000378:metabolism
D001616:beta-Galactosidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium