Metabolic efficiency promotes protection from pressure overload in hearts expressing slow skeletal troponin I.
Metabolic efficiency promotes protection from pressure overload in hearts expressing slow skeletal troponin I.
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DOI：
10.1161/circheartfailure.114.001496
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发表时间：
2015-01
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影响因子：
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通讯作者：
Lewandowski ED
中科院分区：
文献类型：
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作者：
Carley AN;Taglieri DM;Bi J;Solaro RJ;Lewandowski ED
衰竭的心脏表现出糖酵解流量的增加，而葡萄糖氧化的相应增加并不能与之匹配。这种错配导致失血性通量增加和低效的葡萄糖代谢。我们之前发现表达胎儿肌钙蛋白I亚型(SsTnI)的成年转基因小鼠心脏可以通过增加糖酵解来保护其免受缺血。在本研究中，我们研究了表达ssTnI的成年小鼠心脏对慢性压力超负荷的代谢反应。在2-3个月龄时，ssTnI小鼠或其非转基因(NTG)仔鼠发生了主动脉缩窄(TAC)。TAC使NTG心脏大小增加25%，而ssTnI心脏仅增加7%(P<；0.05)。NTG TAC患者出现舒张期功能障碍(65%)，而ssTnI TAC患者E/A比值明显降低。NTG-TAC小鼠离体灌流心脏表现为心功能降低，Pcr：ATP降低16%，而ssTnI-TAC心脏维持心功能和能量负荷。与NTG TAC相比，ssTnI TAC显著增加葡萄糖氧化，但损害棕榈酸酯氧化，从而阻止NTG TAC心脏再生障碍的增加。葡萄糖氧化增加是通过减少PDK4的表达，使PDH与抗坏血酶竞争丙酮酸羧化而实现的。在ssTnI-Tg小鼠心脏中，单个胎儿肌丝蛋白在成年期的表达诱导了PDK对压力超负荷的基因表达反应的下调。在TAC过程中，sTnI中丙酮酸氧化升高的结果是减少了抗逆流量，改善了葡萄糖氧化的低效，对心脏失代偿具有能量和功能保护作用。
The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In the present study we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. At 2–3 months of age ssTnI mice or their nontransgenic (NTG) littermates underwent aortic constriction (TAC). TAC induced a 25% increase in NTG heart size but only a 7% increase in ssTnI hearts (P<0.05). NTG TAC developed diastolic dysfunction (65% increased E/A ratio), while the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from NTG TAC mice showed reduced cardiac function and reduced PCr:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting NTG TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in NTG TAC hearts. Elevated glucose oxidation was mediated by a reduction in PDK4 expression, enabling PDH to compete against anaplerotic enzymes for pyruvate carboxylation. Expression of a single fetal myofilament protein into adulthood in the ssTnI-TG mouse heart induced downregulation of the gene expression response for PDK to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.