Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Japan.
Clinical Pharmacology Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan.
Cells. 2023 Dec 30;13(1):87. doi: 10.3390/cells13010087.
Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed. Evidence indicating that inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may be cardioprotective has been accumulating. Thus, we focused on vitamin K and used its framework as a new PDK4 inhibitor skeleton to synthesize new PDK4 inhibitors that show higher activity than the existing PDK4 inhibitor, dichloroacetic acid, and tested their cardioprotective effects on a mouse heart failure model. Among these inhibitors, PDK4 inhibitor improved EF the most, even though it did not reverse cardiac fibrosis or wall thickness. This novel, potent PDK4 inhibitor may improve EF of failing hearts by regulating bioenergetics via activation of the tricarboxylic acid cycle.
射血分数降低的心力衰竭（HFrEF）的特征不仅是左心室射血分数（EF）降低，而且还伴有呼吸困难、疲劳和水肿等症状。已经确立了几种药物干预措施。然而，仍然需要针对新的病理生理机制的治疗方法。越来越多的证据表明，抑制丙酮酸脱氢酶激酶 4（PDK4）可能具有心脏保护作用。因此，我们专注于维生素 K，并将其作为一种新的 PDK4 抑制剂骨架来合成新型 PDK4 抑制剂，这些抑制剂的活性高于现有的 PDK4 抑制剂二氯乙酸，并在小鼠心力衰竭模型上测试了它们的心脏保护作用。在这些抑制剂中，PDK4 抑制剂改善 EF 的效果最明显，尽管它没有逆转心脏纤维化或壁厚度。这种新型、有效的 PDK4 抑制剂可能通过激活三羧酸循环来调节生物能量学，从而改善衰竭心脏的 EF。
