title: Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins.
abstract: 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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02114, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakata
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakata
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sakata
authors.forename: Elie R
authors.initials: ER
authors.lastname: Chemaly
authors.forename: Li Fan
authors.initials: LF
authors.lastname: Liang
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tsuji
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takewa
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Richard
authors.initials: R
authors.lastname: Peluso
authors.forename: Krisztina
authors.initials: K
authors.lastname: Zsebo
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: 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
chemical_list: D001616:beta-Galactosidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium