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J Thromb Haemost. 2013 Aug;11(8):1454-63. doi: 10.1111/jth.12314.

Potent cardioprotection from ischemia-reperfusion injury by a two-domain fusion protein comprising annexin V and Kunitz protease inhibitor.

Author information

1
Division of Thoracic & Cardiovascular Surgery, Chang Gung Memorial Hospital-Keelung, Keelung, Taiwan. yehccl@cgmh.org.tw

Abstract

BACKGROUND:

Considerable evidence suggests that coagulation proteases (tissue factor [TF]/activated factor VII [FVIIa]/FXa/thrombin) and their target protease activated receptors (PAR-1/PAR-2) play important roles in myocardial ischemia-reperfusion (I-R) injury. We hypothesized that localized inhibition of TF/FVIIa on the membrane surfaces of ischemic cells could effectively block coagulation cascade and subsequent PAR-1/PAR-2 cell signaling, thereby protecting the myocardium from I-R injury.

OBJECTIVES:

We recently developed an annexin V-Kunitz inhibitor fusion protein (ANV-6L15) that could specifically bind to anionic phospholipids on the membrane surfaces of apoptotic cells and efficiently inhibit the membrane-anchored TF/FVIIa. In this study, we investigated the cardioprotective effect of ANV-6L15 in a rat cardiac I-R model in comparison with that of hirudin.

METHODS:

Left coronary artery occlusion was maintained for 45 min followed by 4 h of reperfusion in anesthetized Sprague-Dawley rats. One minute before or 2 min after coronary ligation, rats received an intravenous bolus injection of ANV-6L15 (2.5-250 μg kg(-1) ), vehicle, or hirudin via bolus injection and continuous infusion.

RESULTS AND CONCLUSIONS:

ANV-6L15 dose-dependently reduced infarct size by up to 87% and decreased plasma levels of cardiac troponin I, tumor necrosis factor-α, and soluble intercellular adhesion molecule-1, by up to 97%, 96%, and 66%, respectively, with little impact on the coagulation parameters. ANV-6L15 also ameliorated hemodynamic derangements, attenuated neutrophil infiltration and reduced Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cardiomyocytes. Hirudin was less efficacious even at supraclinical dose. ANV-6L15 confers exceptionally potent cardioprotection and is a promising drug candidate for the prevention of myocardial I-R injury.

KEYWORDS:

annexin V; apoptosis; cardioprotective agents; ischemia-reperfusion injury; proteinase-activated; receptors

PMID:
23746209
PMCID:
PMC3752160
DOI:
10.1111/jth.12314
[Indexed for MEDLINE]
Free PMC Article
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