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Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart

R Costa1, A Morrison, J Wang

  • 1Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA.

Journal of Thrombosis and Haemostasis : JTH
|June 29, 2012
PubMed
Abstract

Insights

Activated protein C (APC) protects the heart from ischemia/reperfusion (I/R) injury by enhancing glucose metabolism. A modified APC (APC-2Cys) shows greater benefits, potentially offering a safe treatment for ischemic heart disease.

Area of Science:

  • Cardiovascular Research
  • Metabolic Signaling
  • Ischemia/Reperfusion Injury

Background:

  • Modulating energy substrate metabolism is a potential therapeutic strategy for ischemia/reperfusion (I/R) injury.
  • AMP-activated protein kinase (AMPK) is a key regulator of metabolic pathways during myocardial ischemia.
  • Activated protein C (APC) demonstrates cardioprotection against I/R injury by enhancing AMPK signaling.

Purpose of the Study:

  • To investigate if APC's modulation of substrate metabolism contributes to its cardioprotective effects against I/R injury.
  • To compare the metabolic effects of wild-type APC and a signaling-proficient mutant (APC-2Cys) on the ischemic heart.

Main Methods:

  • Utilized an ex vivo working mouse heart perfusion system.
  • Assessed the impact of APC and APC-2Cys on glucose transport and substrate oxidation in ischemic hearts.
  • Evaluated autophagic flux following I/R in response to APC treatment.

Main Results:

  • Both APC and APC-2Cys increased glucose uptake and oxidation by promoting GLUT4 translocation to the cell membrane.
  • APC-2Cys exhibited a significantly higher augmentation of metabolic pathways compared to wild-type APC during I/R.
  • APC-2Cys markedly attenuated fatty acid oxidation by 80% during I/R, unlike wild-type APC.

Conclusions:

  • APC provides cardioprotection against I/R injury by favoring glucose oxidation over fatty acid oxidation.
  • APC-2Cys demonstrates superior metabolic modulation and may serve as a promising therapeutic agent for ischemic heart disease without bleeding risks.

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