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Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart
Author(s) -
COSTA R.,
MORRISON A.,
WANG J.,
MANITHODY C.,
LI J.,
REZAIE A. R.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2012.04833.x
Subject(s) - ampk , glut4 , autophagy , reperfusion injury , pharmacology , ischemia , glucose uptake , chemistry , beta oxidation , glucose transporter , medicine , protein kinase a , endocrinology , metabolism , biochemistry , kinase , insulin , apoptosis
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 ( P < 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 ( P < 0.05). Intriguingly, APC‐2Cys, but not wild‐type APC, attenuated the I/R‐initiated fatty acid oxidation by 80% ( P < 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.