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


  • Present address: Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA

Alireza R. Rezaie, Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
Tel.: +1 314 977 9240; fax: +1 314 977 9205.
Correspondence: Ji Li, Department of Pharmacology and Toxicology, University at Buffalo-SUNY, Buffalo, NY 14214, USA.
Tel.: +1 716 829 5711; fax: +1 716 829 2801.


Summary.  Background:  Modulation of energy substrate metabolism may constitute a novel therapeutic intervention against ischemia/reperfusion (I/R) injury. AMP-activated protein kinase (AMPK) has emerged as a key regulator of favorable metabolic signaling pathways in response to myocardial ischemia. Recently, we demonstrated that activated protein C (APC) is cardioprotective against ischemia/reperfusion (I/R) injury by augmenting AMPK signaling.

Objectives:  The objective of this study was to determine whether the APC modulation of substrate metabolism contributes to its cardioprotective effect against I/R injury.

Methods:  An ex vivo working mouse heart perfusion system was used to characterize the effect of wild-type APC and its signaling-proficient mutant, APC-2Cys (which has dramatically reduced anticoagulant activity), on glucose transport in the ischemic heart.

Results:  Both APC and APC-2Cys (0.2 μg g−1) augment the ischemic stress-induced translocation of the glucose transporter (GLUT4) to the myocardial cell membrane, leading to increased glucose uptake and glucose oxidation in the ischemic heart (< 0.05 vs. vehicle). Both APC derivatives increased the autophagic flux in the heart following I/R. The activity of APC-2Cys in modulating these metabolic pathways was significantly higher than APC during I/R (< 0.05). Intriguingly, APC-2Cys, but not wild-type APC, attenuated the I/R-initiated fatty acid oxidation by 80% (< 0.01 vs. vehicle).

Conclusions:  APC exerts a cardioprotective effect against I/R injury by preferentially enhancing the oxidation of glucose over fatty acids as energy substrates in the ischemic heart. Given its significantly higher beneficial metabolic modulatory effect, APC-2Cys may be developed as a potential therapeutic drug for treating ischemic heart disease without risk of bleeding.