Schugar Rebecca C, Moll Ashley R, André d'Avignon D, Weinheimer Carla J, Kovacs Attila, Crawford Peter A
Department of Medicine, Center for Cardiovascular Research, Washington University, St. Louis, MO, USA.
Department of Chemistry, Washington University, St. Louis, MO, USA.
Mol Metab. 2014 Aug 13;3(7):754-69. doi: 10.1016/j.molmet.2014.07.010. eCollection 2014 Oct.
Exploitation of protective metabolic pathways within injured myocardium still remains an unclarified therapeutic target in heart disease. Moreover, while the roles of altered fatty acid and glucose metabolism in the failing heart have been explored, the influence of highly dynamic and nutritionally modifiable ketone body metabolism in the regulation of myocardial substrate utilization, mitochondrial bioenergetics, reactive oxygen species (ROS) generation, and hemodynamic response to injury remains undefined.
Here we use mice that lack the enzyme required for terminal oxidation of ketone bodies, succinyl-CoA:3-oxoacid CoA transferase (SCOT) to determine the role of ketone body oxidation in the myocardial injury response. Tracer delivery in ex vivo perfused hearts coupled to NMR spectroscopy, in vivo high-resolution echocardiographic quantification of cardiac hemodynamics in nutritionally and surgically modified mice, and cellular and molecular measurements of energetic and oxidative stress responses are performed.
While germline SCOT-knockout (KO) mice die in the early postnatal period, adult mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) remarkably exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to a ketogenic diet. Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. To determine the role of ketone body oxidation in the remodeling ventricle, we induced pressure overload injury by performing transverse aortic constriction (TAC) surgery in SCOT-Heart-KO and αMHC-Cre control mice. While TAC increased left ventricular mass equally in both groups, at four weeks post-TAC, myocardial ROS abundance was increased in myocardium of SCOT-Heart-KO mice, and mitochondria and myofilaments were ultrastructurally disordered. Eight weeks post-TAC, left ventricular volume was markedly increased and ejection fraction was decreased in SCOT-Heart-KO mice, while these parameters remained normal in hearts of control animals.
These studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and suggest that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart.
开发受损心肌内的保护性代谢途径仍是心脏病中一个未明确的治疗靶点。此外，虽然已经探讨了脂肪酸和葡萄糖代谢改变在衰竭心脏中的作用，但高度动态且营养可调节的酮体代谢对心肌底物利用、线粒体生物能量学、活性氧（ROS）生成以及对损伤的血流动力学反应的影响仍不明确。
在此，我们使用缺乏酮体终末氧化所需酶琥珀酰辅酶A：3-氧代酸辅酶A转移酶（SCOT）的小鼠，以确定酮体氧化在心肌损伤反应中的作用。通过与核磁共振波谱联用的离体灌注心脏中的示踪剂输送、对营养和手术修饰小鼠的心脏血流动力学进行体内高分辨率超声心动图定量，以及对能量和氧化应激反应进行细胞和分子测量。
虽然种系SCOT基因敲除（KO）小鼠在出生后早期死亡，但成年心肌细胞特异性缺失SCOT（SCOT-心脏-KO）的小鼠在酮症期间（包括禁食和坚持生酮饮食），明显没有明显的代谢异常，左心室质量无差异，收缩功能也无损害。当输送酮体但无法氧化时，心肌脂肪酸氧化增加。为了确定酮体氧化在心室重塑中的作用，我们通过在SCOT-心脏-KO和αMHC-Cre对照小鼠中进行横向主动脉缩窄（TAC）手术诱导压力超负荷损伤。虽然TAC在两组中均使左心室质量同等增加，但在TAC后四周，SCOT-心脏-KO小鼠心肌中的心肌ROS丰度增加，线粒体和肌丝超微结构紊乱。TAC后八周，SCOT-心脏-KO小鼠的左心室容积明显增加，射血分数降低，而对照动物心脏中的这些参数保持正常。
这些研究证明了心肌酮代谢协调心肌对压力超负荷反应的能力，并表明酮体氧化可能是受损心脏中自由基稳态和血流动力学维持的重要因素。
