Abstract 12821: Short Interfering RNA-Mediated Knockdown Of Glucose-6-Phosphate Dehydrogenase Impairs Cardiac Contractile Performance and Efficiency in Conscious Dogs

The oxidative pentose phosphate pathway (oxPPP) generates cytosolic NADPH and has been found critically important for redox homeostasis and function of isolated cardiomyocytes. However, no studies have explored the functional consequences of oxPPP downregulation in the intact heart. We tested whether knocking down glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme in the oxPPP, impairs cardiac performance, in vivo. In 5 conscious, chronically instrumented dogs, hemodynamics and cardiac oxygen consumption were measured at baseline and during beta-adrenergic stress (5, 10 and 15 µg/kg/min dobutamine, i.v.). A balloon-tip catheter was then inserted into the coronary sinus under fluoroscopy for cardio-selective delivery, in retrograde fashion, of 1013 p.f.u. adenoviral vectors carrying DNA encoding for anti-G6PD siRNA. Eight days after adenovirus delivery, dogs underwent the same protocol described above, with an additional infusion of [U-13C]-glucose. 13C-NMR spectroscopy was perfor...