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Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in

Haobo Li1, Weifeng Yao2, Zipeng Liu3

  • 1State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.

Diabetes
|January 1, 2016
PubMed

Insights

Ischemic postconditioning protects the heart by activating mitochondrial STAT3 via adiponectin signaling. This protective effect is lost in diabetes due to impaired adiponectin receptor and caveolin-3 signaling, highlighting potential therapeutic targets for myocardial ischemia-reperfusion injury.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Diabetology

Background:

  • Ischemic postconditioning (IPo) protects against myocardial ischemia-reperfusion injury (MIRI) by activating signal transducer and activator of transcription 3 (STAT3).
  • Cardioprotection by IPo is diminished in diabetes, coinciding with impaired cardiac STAT3 activation and reduced adiponectin (APN) levels.
  • The precise mechanisms underlying the loss of IPo's cardioprotective effects in diabetes remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of APN, mitochondrial STAT3 (mitoSTAT3), and the APN receptor 1 (AdipoR1)/caveolin-3 (Cav3) pathway in IPo-mediated cardioprotection.
  • To investigate how diabetes impairs this signaling cascade and abrogates the protective effects of IPo.
  • To identify potential therapeutic strategies for MIRI in diabetic patients.

Main Methods:

  • Utilized wild-type and APN knockout (Adipo(-/-)) mice subjected to myocardial ischemia-reperfusion (I/R) injury.
  • Employed isolated cardiomyocytes and diabetic rat models (4- and 8-week duration) to assess IPo effects.
  • Investigated the involvement of APN, AdipoR1, STAT3, mitoSTAT3, and Cav3 through gene knockdown, recombinant protein administration, and disruption of signaling pathways.

Main Results:

  • IPo increased cardiomyocyte-derived APN, activated mitoSTAT3, improved mitochondrial function, and attenuated MIRI in wild-type mice, but not in Adipo(-/-) mice.
  • Recombinant APN restored hypoxic postconditioning-induced protection in Adipo(-/-) cardiomyocytes, an effect dependent on STAT3, AdipoR1, and Cav3.
  • IPo restored cardioprotection in early-stage diabetic rats (4 weeks) via functional AdipoR1/Cav3 interaction, but this was lost in later-stage diabetes (8 weeks) due to severely reduced Cav3 and impaired AdipoR1/Cav3 signaling.

Conclusions:

  • IPo confers cardioprotection by activating mitoSTAT3 through the APN/AdipoR1/Cav3 pathway.
  • Diabetes impairs IPo-mediated cardioprotection due to a breakdown in the APN/AdipoR1/Cav3 signaling axis.
  • Targeting APN and restoring AdipoR1/Cav3 signaling concurrently may offer a promising therapeutic approach for treating MIRI in diabetic individuals.

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