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 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 (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 + βgal” 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 ∼ 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.