Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
Circ Heart Fail. 2012 Jul 1;5(4):493-503. doi: 10.1161/CIRCHEARTFAILURE.112.966705. Epub 2012 Jun 15.
Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the α-adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor.
Ang II (1.5 mg·kg(-1)·day(-1)) or PE (40 mg·kg(-1)·day(-1)) was administered to 9-week-old male C57/BL6 wild-type mice for 14 days via implanted microosmotic pumps. Echocardiography showed concentric hypertrophy and diastolic dysfunction, with preserved systolic function in Ang II- and PE-treated mice. Ang II induced marked reduction in cardiac glucose oxidation and lactate oxidation, with no change in glycolysis and fatty acid β-oxidation. Tricarboxylic acid acetyl coenzyme A production and ATP production were reduced in response to Ang II. Cardiac pyruvate dehydrogenase kinase 4 expression was upregulated by Ang II and PE, resulting in a reduction in the pyruvate dehydrogenase activity, the rate-limiting step for carbohydrate oxidation. Pyruvate dehydrogenase kinase 4 upregulation correlated with the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway in response to Ang II. Ang II type 1 receptor blockade normalized the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway and prevented the reduction in glucose oxidation but increased fatty acid oxidation.
Ang II- and PE-induced hypertrophy and diastolic dysfunction is associated with reduced glucose oxidation because of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F-induced upregulation of pyruvate dehydrogenase kinase 4, and targeting these pathways may provide novel therapy for heart failure with normal ejection fraction.
肾素-血管紧张素和交感神经系统的激活可能改变心脏能量底物的偏好，从而导致射血分数正常的心力衰竭的进展。我们评估了血管紧张素 II（Ang II）和α-肾上腺素能激动剂苯肾上腺素（PE）对肥大和舒张功能障碍实验模型中心脏能量代谢的定性和定量影响，以及 Ang II 型 1 受体的作用。
通过植入的微渗透泵，将 Ang II（1.5 mg·kg(-1)·day(-1)）或 PE（40 mg·kg(-1)·day(-1)）施用于 9 周龄雄性 C57/BL6 野生型小鼠 14 天。超声心动图显示，Ang II 和 PE 处理的小鼠发生向心性肥大和舒张功能障碍，而收缩功能正常。Ang II 引起心脏葡萄糖氧化和乳酸氧化明显减少，而糖酵解和脂肪酸 β-氧化没有变化。三羧酸乙酰辅酶 A 生成和 ATP 生成减少对 Ang II 有反应。Ang II 和 PE 上调丙酮酸脱氢酶激酶 4 的表达，导致丙酮酸脱氢酶活性降低，这是碳水化合物氧化的限速步骤。丙酮酸脱氢酶激酶 4 的上调与 Ang II 反应中环细胞/细胞周期蛋白依赖性激酶-视网膜母细胞瘤蛋白-E2F 通路的激活相关。Ang II 型 1 受体阻断可使 cyclin/细胞周期蛋白依赖性激酶-视网膜母细胞瘤蛋白-E2F 通路的激活正常化，并防止葡萄糖氧化减少，但增加脂肪酸氧化。
Ang II 和 PE 诱导的肥大和舒张功能障碍与葡萄糖氧化减少有关，这是由于 cyclin/细胞周期蛋白依赖性激酶-视网膜母细胞瘤蛋白-E2F 诱导的丙酮酸脱氢酶激酶 4 上调所致，针对这些途径可能为射血分数正常的心力衰竭提供新的治疗方法。
