Quillen College of Medicine, Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, 37614, USA.
Cardiovasc Drugs Ther. 2023 Oct;37(5):1021-1026. doi: 10.1007/s10557-022-07341-z. Epub 2022 Apr 30.
Previous work suggests that Dihydroorotate dehydrogenase (DHODH) inhibition via teriflunomide (TERI) may provide protection in multiple disease models. To date, little is known about the effect of TERI on the heart. This study was performed to assess the potential effects of TERI on cardiac ischemia reperfusion injury.
Male and female rat hearts were subjected to global ischemia (25 min) and reperfusion (120 min) on a Langendorff apparatus. Hearts were given either DMSO (VEH) or teriflunomide (TERI) for 5 min prior to induction of ischemia and during the reperfusion period. Left ventricular pressure, ECG, coronary flow, and infarct size were determined using established methods. Mitochondrial respiration was assessed via respirometry.
Perfusion of hearts with TERI led to no acute effects in any values measured across 500 pM-50 nM doses. However, following ischemia-reperfusion injury, we found that 50 nM TERI-treated hearts had an increase in myocardial infarction (p < 0.001). In 50 nM TERI-treated hearts, we also observed a marked increase in the severity of contracture (p < 0.001) at an earlier time-point (p = 0.004), as well as reductions in coronary flow (p = 0.037), left ventricular pressure development (p = 0.025), and the rate-pressure product (p = 0.008). No differences in mitochondrial respiration were observed with 50 nM TERI treatment (p = 0.24-0.87).
This study suggests that treatment with TERI leads to more negative outcomes following cardiac ischemia reperfusion, and administration of TERI to at-risk populations should receive special considerations.
先前的研究表明，通过特立氟胺（TERI）抑制二氢乳清酸脱氢酶（DHODH）可能在多种疾病模型中提供保护。迄今为止，人们对特立氟胺对心脏的影响知之甚少。本研究旨在评估特立氟胺对心肌缺血再灌注损伤的潜在影响。
雄性和雌性大鼠心脏在 Langendorff 仪器上进行整体缺血（25 分钟）和再灌注（120 分钟）。在诱导缺血前和再灌注期间，心脏给予 DMSO（VEH）或特立氟胺（TERI）5 分钟。使用已建立的方法测定左心室压力、心电图、冠脉流量和梗死面积。通过呼吸测定法评估线粒体呼吸。
在 500pM-50nM 剂量范围内，TERI 灌注对所有测量值均无急性影响。然而，在缺血再灌注损伤后，我们发现 50nM TERI 处理的心脏心肌梗死增加（p<0.001）。在 50nM TERI 处理的心脏中，我们还观察到收缩更为严重（p<0.001），且发生更早（p=0.004），以及冠脉流量（p=0.037）、左心室压力发展（p=0.025）和压力-速率产物（p=0.008）降低。用 50nM TERI 处理时，线粒体呼吸没有差异（p=0.24-0.87）。
本研究表明，特立氟胺治疗后会导致心脏缺血再灌注后出现更负面的结果，因此，高危人群应特别考虑特立氟胺的给药。
