Exogenous nicotinamide adenine dinucleotide administration alleviates ischemia/reperfusion-induced oxidative injury in isolated rat hearts via Sirt5-SDH-succinate pathway

Eur J Pharmacol. 2019 Sep 5;858:172520. doi: 10.1016/j.ejphar.2019.172520. Epub 2019 Jul 3.


The metabolic disorder of succinate in myocardial tissue during ischemia-reperfusion can lead to the myocardial oxidative injury. The activation of succinate dehydrogenase (SDH) plays a vital role in the process. Silent information regulator 5 (Sirt5), a nicotinamide adenine dinucleotide (NAD)-dependent desuccinylase, desuccinylates and inactivates SDH thus exerting a protective effect on the myocardium. This research was designed to investigate whether exogenous NAD protects the myocardium from the ischemia-reperfusion-induced oxidative injury through regulating Sirt5-SDH pathway and succinate metabolism. We first found that myocardial total NAD level was remarkably increased with NAD treatment (10 mg/kg) for 14 days. NAD administration significantly decreased the lactate dehydrogenase (LDH) level in coronary leakage, decreased the malondialdehyde (MDA) level and increased the reduced glutathione/oxidized glutathione disulfide ratio (GSH/GSSG) in myocardial tissue. In addition, NAD treatment effectively attenuated the depression of cardiac function in the isolated rat hearts after ischemia-reperfusion. Furthermore, we found that exogenous NAD attenuated the succinate accumulation during ischemia and decreased its depleting rate during reperfusion. We also found that NAD administration had no obvious effects on myocardial Sirt5 and SDH-a expressions. However, the results of immunofluorescence showed that Sirt5 and SDH-a interacted in ischemia-reperfused myocardium. Utilizing co-immunoprecipitation method, we found that NAD administration promoted the Sirt5 and SDH-a interaction and decreased the succinylation level of SDH-a. These results implied that exogenous NAD administration promoted Sirt5-mediated SDH-a desuccinylation and decreased the activity of SDH-a, which attenuated the succinate accumulation during ischemia and its depleting rate during reperfusion and finally alleviated reactive oxygen species generation.

Keywords: Myocardial ischemia-reperfusion; Nicotinamide adenine dinucleotide; Sirt5; Succinate; Succinate dehydrogenase.

MeSH terms

  • Animals
  • Male
  • Malondialdehyde / metabolism
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • NAD / administration & dosage
  • NAD / pharmacology*
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Sirtuins / metabolism*
  • Succinate Dehydrogenase / metabolism*
  • Succinic Acid / metabolism*


  • Reactive Oxygen Species
  • NAD
  • Malondialdehyde
  • Succinic Acid
  • Succinate Dehydrogenase
  • SIRT5 protein, rat
  • Sirtuins