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JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial

Yang Yang1, Weixun Duan, Zhenxiao Jin

  • 1Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Journal of Pineal Research
|June 26, 2013
PubMed

Insights

Melatonin pretreatment protects the heart from ischemia/reperfusion injury (IRI) by reducing mitochondrial oxidative damage. This protective effect is mediated through the activation of the JAK2/STAT3 signaling pathway.

Area of Science:

  • Cardiovascular Science
  • Mitochondrial Biology
  • Pharmacology

Background:

  • Ischemia/reperfusion injury (IRI) is a major cause of cardiovascular damage, leading to mitochondrial oxidative stress.
  • The Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial in protecting against myocardial IRI.
  • Melatonin is known for its potent anti-IRI activity and potential to modulate the JAK2/STAT3 pathway.

Purpose of the Study:

  • To investigate the cardioprotective effects of melatonin pretreatment on myocardial IRI.
  • To elucidate the underlying mechanism involving the JAK2/STAT3 signaling pathway and mitochondrial oxidative stress.

Main Methods:

  • Isolated rat hearts and cardiomyocytes were pretreated with melatonin, followed by exposure to ischemia/reperfusion (IR).
  • The JAK2/STAT3 signaling pathway was inhibited using AG490 (a JAK2/STAT3 inhibitor) or JAK2 siRNA.
  • Cardiac function, infarct size, apoptosis, cell damage markers, mitochondrial redox potential, and oxidative stress markers (SOD, H2O2, MDA) were assessed.

Main Results:

  • Melatonin pretreatment significantly improved postischemic cardiac function, reduced infarct size, decreased apoptosis, and lowered lactate dehydrogenase release.
  • Melatonin upregulated Bcl2 and downregulated Bax, indicating an anti-apoptotic effect.
  • Inhibition of JAK2/STAT3 signaling (using AG490 or JAK2 siRNA) abolished the cardioprotective effects of melatonin.
  • Melatonin preserved mitochondrial redox potential, increased SOD activity, and reduced H2O2 and MDA formation, indicating attenuation of mitochondrial oxidative damage.
  • The beneficial effects of melatonin on mitochondrial function were reversed by JAK2/STAT3 inhibition.

Conclusions:

  • Melatonin pretreatment effectively attenuates myocardial IRI by mitigating IR-induced mitochondrial oxidative damage.
  • The cardioprotective mechanism of melatonin involves the activation of the JAK2/STAT3 signaling pathway.
  • Targeting melatonin and the JAK2/STAT3 pathway presents a promising therapeutic strategy for managing IRI.
Keywords:
AG490JAK2/STAT3 signalingcardio-protectionischemia/reperfusion injurymelatoninmitochondrial oxidative damage

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