Alexander 2022 Cardiovasc Drugs Ther

Alexander ED, Aldridge JL, Burleson TS, Frasier CR (2022) Teriflunomide treatment exacerbates cardiac ischemia reperfusion injury in isolated rat hearts. https://doi.org/10.1007/s10557-022-07341-z

» Cardiovasc Drugs Ther 37:1021-26. PMID: 35488973 Open Access

Alexander Emily Davis,  Aldridge Jessa L,  Burleson T Samuel,  Frasier Chad R (2022) Cardiovasc Drugs Ther

Abstract: 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. • Keywords: Dihydroorotate dehydrogenase, Infarct, Ischemia reperfusion, Teriflunomide • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Ischemia-reperfusion  Organism: Rat  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 

2022-11