Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux.
Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux.
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DOI：
10.1161/jaha.113.000355
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发表时间：
2013-11-04
影响因子：
5.4
通讯作者：
Baines CP
中科院分区：
文献类型：
--
作者：
McCommis KS;Douglas DL;Krenz M;Baines CP
己糖激酶-2（HK 2）磷酸化葡萄糖，这是几乎所有葡萄糖利用途径的起始步骤。心脏肥大与葡萄糖代谢增加和脂肪酸代谢减少有关。最近的证据表明，增加葡萄糖利用是对肥大期间下调的脂肪酸代谢的补偿，实际上是有益的。因此，我们假设通过HK 2过表达增加葡萄糖利用可以减少心肌肥厚。心脏特异性HK 2过表达的小鼠对异丙肾上腺素的反应显示肥大减轻。用HK 2腺病毒感染的新生大鼠心室肌细胞（NRVMs）同样显示对苯肾上腺素反应的肥大减少。肥大增加活性氧（ROS）水平，这是减弱HK 2过表达，从而减少NRVM肥大和死亡。HK 2似乎通过磷酸戊糖途径调节ROS，因为脱氢表雄酮抑制葡萄糖-6-磷酸脱氢酶降低了HK 2减少ROS和肥大的能力。这些结果表明，HK 2通过增加磷酸戊糖途径通量减少ROS积累来减轻心肌肥大。
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. 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. These results suggest that HK2 attenuates cardiac hypertrophy by decreasing ROS accumulation via increased pentose phosphate pathway flux.