Restoration of Mechanical and Energetic Function in Failing Aortic-Banded Rat Hearts by Gene Transfer of Calcium Cycling Proteins

摘要

The aim of this study was to examine whether short- and long-term gene transfer of Ca²⁺ handling proteins restore left ventricular (LV) mechanoenergetics in aortic banding-induced failing hearts. Aortic banded rats received recombinant adenoviruses carrying sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) (Banding+SERCA), parvalbumin (Banding+Parv) or β-galactosidase (Banding+βgal), 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+βgal” and “Banding+saline” groups showed lower end-systolic pressure at 0.1 ml intraballoon water (ESP0.1), higher end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) and slower LV relaxation rate, compared with “Normal” and “Sham”. However, “Banding+SERCA” and “Banding+Parv” showed high ESP0.1, low EDP0.1, and fast LV relaxation rate. In “Banding”, “Banding+βgal” and “Banding+saline”, slope of relation between cardiac oxygen consumption and systolic pressure-volume area, O2 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, O2 cost of LV contractility in the 3 control banding groups was ∼3 times higher than normal value, whereas O2 cost of contractility in “Banding+SERCA”, “Banding+AAV.SERCA” and “Banding+Parv” was as low as normal value. Thus, high O2 osts 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.