Department of Internal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.
Department of Internal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio
J Pharmacol Exp Ther. 2019 Apr;369(1):55-64. doi: 10.1124/jpet.118.254557. Epub 2019 Jan 11.
Inhibition of and genetic deletion of the NAD(P) hydrolase [NAD(P)ase] CD38 have been shown to protect against ischemia/reperfusion (I/R) injury in rat and mouse hearts. CD38 has been shown to enhance salvage of NADP(H), which in turn prevents impairment of endothelial nitric oxide synthase function, a hallmark of endothelial dysfunction. Despite growing evidence for a role of CD38 in postischemic injury, until recently there had been a lack of potent CD38 inhibitors. Recently, a new class of thiazoloquin(az)olin(on)e compounds were identified as highly potent and specific CD38 inhibitors. Herein, we investigate the ability of one of these compounds, 78c, to inhibit CD38 and protect the heart in an ex vivo model of myocardial I/R injury. The potency and mechanism of CD38 inhibition by 78c was assessed in vitro using recombinant CD38. The dose-dependent tissue uptake of 78c in isolated mouse hearts was determined, and high tissue permeability of 78c was observed when delivered in perfusate. Treatment of hearts with 78c was protective against both postischemic endothelial and cardiac myocyte injury, with preserved nitric oxide synthase-dependent vasodilatory and contractile function, respectively. Myocardial infarction was also significantly decreased in 78c-treated hearts, with preserved levels of high-energy phosphates. Protective effects peaked at 10 M treatment, and similar protection without toxicity was seen at 5-fold higher doses. Overall, 78c was shown to be a potent and biologically active CD38 inhibitor with favorable tissue uptake and marked protective effects against I/R injury with enhanced preservation of contractile function, coronary flow, and decreased infarction.
抑制 NAD(P)水解酶 [NAD(P)ase] CD38 的表达或基因敲除已被证明可防止大鼠和小鼠心脏的缺血/再灌注 (I/R) 损伤。CD38 已被证明可增强 NADP(H) 的回收，这反过来又可防止内皮型一氧化氮合酶功能受损，而后者是内皮功能障碍的标志。尽管越来越多的证据表明 CD38 在缺血后损伤中起作用，但直到最近，仍然缺乏有效的 CD38 抑制剂。最近，一类新的噻唑并喹啉（氮杂）啉化合物被鉴定为高度有效和特异的 CD38 抑制剂。在此，我们研究了其中一种化合物 78c 抑制 CD38 的能力，并在体外心肌 I/R 损伤模型中研究了它对心脏的保护作用。使用重组 CD38 在体外评估了 78c 对 CD38 的抑制作用及其作用机制。测定了 78c 在分离的小鼠心脏中的剂量依赖性组织摄取，并观察到在灌流液中给予时 78c 具有很高的组织通透性。用 78c 处理心脏可防止缺血后内皮和心肌细胞损伤，分别保持一氧化氮合酶依赖性血管舒张和收缩功能。用 78c 处理的心脏也显著减少了心肌梗死，同时保持高能磷酸水平。在 10 μM 治疗时，保护作用达到峰值，在 5 倍更高剂量时也观察到类似的保护作用而无毒性。总体而言，78c 被证明是一种有效的 CD38 抑制剂，具有良好的组织摄取和显著的 I/R 损伤保护作用，同时增强了收缩功能、冠脉流量的保存，并减少了梗死。
