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Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux.

Authors: McCommis, KS  Douglas, DL  Krenz, M  Baines, CP 
Citation: McCommis KS, etal., J Am Heart Assoc. 2013 Nov 4;2(6):e000355. doi: 10.1161/JAHA.113.000355.
Pubmed: (View Article at PubMed) PMID:24190878
DOI: Full-text: DOI:10.1161/JAHA.113.000355

BACKGROUND: The enzyme hexokinase-2 (HK2) 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 HK2 overexpression would decrease cardiac hypertrophy. METHODS AND RESULTS: Mice with cardiac-specific HK2 overexpression displayed decreased hypertrophy in response to isoproterenol. Neonatal rat ventricular myocytes (NRVMs) infected with an HK2 adenovirus similarly displayed decreased hypertrophy in response to phenylephrine. Hypertrophy increased reactive oxygen species (ROS) levels, which were attenuated by HK2 overexpression, thereby decreasing NRVM hypertrophy and death. HK2 appears to modulate ROS via the pentose phosphate pathway, as inhibition of glucose-6-phosphate dehydrogenase with dehydroepiandrosterone decreased the ability of HK2 to diminish ROS and hypertrophy. CONCLUSIONS: These results suggest that HK2 attenuates cardiac hypertrophy by decreasing ROS accumulation via increased pentose phosphate pathway flux.

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CRRD Object Information
CRRD ID: 10449133
Created: 2015-12-18
Species: All species
Last Modified: 2015-12-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.