Sorokina Natalia, O'Donnell J Michael, McKinney Ronald D, Pound Kayla M, Woldegiorgis Gebre, LaNoue Kathryn F, Ballal Kalpana, Taegtmeyer Heinrich, Buttrick Peter M, Lewandowski E Douglas
Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
Circulation. 2007 Apr 17;115(15):2033-41. doi: 10.1161/CIRCULATIONAHA.106.668665. Epub 2007 Apr 2.
Transport rates of long-chain free fatty acids into mitochondria via carnitine palmitoyltransferase I relative to overall oxidative rates in hypertrophied hearts remain poorly understood. Furthermore, the extent of glucose oxidation, despite increased glycolysis in hypertrophy, remains controversial. The present study explores potential compensatory mechanisms to sustain tricarboxylic acid cycle flux that resolve the apparent discrepancy of reduced fatty acid oxidation without increased glucose oxidation through pyruvate dehydrogenase complex in the energy-poor, hypertrophied heart.
We studied flux through the oxidative metabolism of intact adult rat hearts subjected to 10 weeks of pressure overload (hypertrophied; n=9) or sham operation (sham; n=8) using dynamic 13C-nuclear magnetic resonance. Isolated hearts were perfused with [2,4,6,8,10,12,14,16-(13)C8] palmitate (0.4 mmol/L) plus glucose (5 mmol/L) in a 14.1-T nuclear magnetic resonance magnet. At similar tricarboxylic acid cycle rates, flux through carnitine palmitoyltransferase I was 23% lower in hypertrophied (P<0.04) compared with sham hearts and corresponded to a shift toward increased expression of the L-carnitine palmitoyltransferase I isoform. Glucose oxidation via pyruvate dehydrogenase complex did not compensate for reduced palmitate oxidation rates. However, hypertrophied rats displayed an 83% increase in anaplerotic flux into the tricarboxylic acid cycle (P<0.03) that was supported by glycolytic pyruvate, coincident with increased mRNA transcript levels for malic enzyme.
In cardiac hypertrophy, fatty acid oxidation rates are reduced, whereas compensatory increases in anaplerosis maintain tricarboxylic acid cycle flux and account for a greater portion of glucose oxidation than previously recognized. The shift away from acetyl coenzyme A production toward carbon influx via anaplerosis bypasses energy, yielding reactions contributing to a less energy-efficient heart.
相对于肥厚心脏中的整体氧化速率，长链游离脂肪酸通过肉碱棕榈酰转移酶I进入线粒体的转运速率仍知之甚少。此外，尽管肥大时糖酵解增加，但葡萄糖氧化的程度仍存在争议。本研究探讨了维持三羧酸循环通量的潜在代偿机制，这些机制解决了能量匮乏的肥大心脏中脂肪酸氧化减少而葡萄糖氧化未增加的明显差异，这一差异是通过丙酮酸脱氢酶复合体体现的。
我们使用动态13C核磁共振研究了完整成年大鼠心脏在经历10周压力超负荷（肥大；n = 9）或假手术（假手术；n = 8）后的氧化代谢通量。在14.1-T核磁共振磁体中，用[2,4,6,8,10,12,14,16-(13)C8]棕榈酸（0.4 mmol/L）加葡萄糖（5 mmol/L）灌注离体心脏。在相似的三羧酸循环速率下，与假手术心脏相比，肥大心脏中通过肉碱棕榈酰转移酶I的通量降低了23%（P<0.04），这与L-肉碱棕榈酰转移酶I同工型表达增加的转变相对应。通过丙酮酸脱氢酶复合体的葡萄糖氧化并未补偿棕榈酸氧化速率的降低。然而，肥大的大鼠进入三羧酸循环的回补通量增加了83%（P<0.03），这由糖酵解产生的丙酮酸支持，同时苹果酸酶的mRNA转录水平增加。
在心脏肥大中，脂肪酸氧化速率降低，而回补的代偿性增加维持了三羧酸循环通量，并且葡萄糖氧化的占比高于先前的认识。从乙酰辅酶A生成向通过回补的碳流入的转变绕过了能量产生反应，导致心脏能量效率降低。
