Cardiac‐specific Hexokinase 2 Overexpression Attenuates Hypertrophy by Increasing Pentose Phosphate Pathway Flux

Abstract

Background The enzyme hexokinase‐2 ( HK 2) phosphorylates glucose, which is the initiating step in virtually all glucose utilization pathways. Cardiac hypertrophy is associated with a switch towards increased glucose metabolism and decreased fatty acid metabolism. Recent evidence suggests that the increased glucose utilization is compensatory to the down‐regulated fatty acid metabolism during hypertrophy and is, in fact, beneficial. Therefore, we hypothesized that increasing glucose utilization by HK 2 overexpression would decrease cardiac hypertrophy. Methods and Results Mice with cardiac‐specific HK 2 overexpression displayed decreased hypertrophy in response to isoproterenol. Neonatal rat ventricular myocytes ( NRVM s) infected with an HK 2 adenovirus similarly displayed decreased hypertrophy in response to phenylephrine. Hypertrophy increased reactive oxygen species (ROS) levels, which were attenuated by HK 2 overexpression, thereby decreasing NRVM hypertrophy and death. HK 2 appears to modulate ROS via the pentose phosphate pathway, as inhibition of glucose‐6‐phosphate dehydrogenase with dehydroepiandrosterone decreased the ability of HK 2 to diminish ROS and hypertrophy. Conclusions These results suggest that HK 2 attenuates cardiac hypertrophy by decreasing ROS accumulation via increased pentose phosphate pathway flux.