Abstract 16187: Reduction of Hexokinase II Exaggerates Cardiac Hypertrophy and Accelerates Transition to Heart Failure via Increased Production of Reactive Oxygen Species
Rationale/Objective: Cardiac hypertrophy is associated with a metabolic switch in substrate utilization from fatty acids to glucose. Hexokinase II, a key enzyme in glucose metabolism, and its binding to mitochondria are important for cardiac response to ischemia, however, their role in cardiac hypertrophy is not known. We hypothesized that a reduction in HKII attenuates the cardiac hypertrophic response through a reduction in glucose metabolism.
Methods/Results: We subjected HKII heterozygous knockout (HKII+/-) mice and wildtype littermates to transverse aortic constriction (TAC). Contrary to our hypothesis, the hypertrophic response was significantly greater in HKII+/- mice. Furthermore, we observed reduced cardiac function and increased mortality in the HKII+/- mice by the 8-week time point, indicating an accelerated transition to heart failure. In primary cultures of neonatal rat cardiomyocytes (NRCM), siRNA knockdown of HKII exacerbated the hypertrophic response to Angiotensin II (AngII) compared to control. The mechanism for this phenomenon is through increased production of reactive oxygen species (ROS), as HKII knockdown increased ROS production after hypertrophic stimulation relative to controls. Treatment of NRCM with the antioxidant N-acetylcysteine (NAC) attenuated the hypertrophic response with HKII knockdown in the presence of AngII. Dissociation of HKII from the mitochondria with a cell permeable peptide resulted in de novo hypertrophy, which was attenuated by NAC, suggesting that mitochondrial binding of HKII is also important for the hypertrophic effect. Further investigation into the source of ROS revealed that HKII knockdown or mitochondrial dissociation resulted in increased mitochondrial permeability transition (MPT) and decreased levels of reduced glutathione. The latter is due to a reduction in NADPH produced by the Pentose Phosphate Pathway (PPP), which is dependent on glucose-6-phosphate, the reaction product of HKII.
Conclusions: Overall, the data suggest that HKII and its mitochondrial binding negatively regulate cardiac hypertrophy by decreasing ROS production through inhibition of mitochondrial permeability and increasing antioxidant defenses via NADPH production.
- © 2011 by American Heart Association, Inc.