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Friday, 09/15/2006 2:49:13 PM

Friday, September 15, 2006 2:49:13 PM

Post# of 19309
Thrombin Increases Cardiomyocyte Acute Cell Death After Ischemia and Reperfusion

[Why did I post this? Because any acute indication where thrombin is bad is theoretically an opening for treatment with antithrombin.]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...

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J Mol Cell Cardiol. 2005 Aug;39(2):277-83.

Mirabet M, Garcia-Dorado D, Ruiz-Meana M, Barrabes JA, Soler-Soler J.

Servicio de Cardiologia, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Thrombin exerts multiple actions on cardiomyocytes leading to increased intracellular Na+ and Ca2+ concentrations, and to activation of a Ca2+-independent PLA2, and has been proposed to favor the genesis of arrhythmias and ischemic injury in acute coronary syndromes. However, the influence of thrombin on cardiomyocyte cell death during ischemia-reperfusion has not been studied.

A beneficial influence of low thrombin concentrations has been described in other cell types. HL-1 cardiomyocytes were subjected to simulated ischemia (SI) and reperfusion (SR) and cell death was assessed by means of LDH release to the incubation media. Thrombin dose-dependently increased cell death in normoxic cells, in cells subjected to SI, and in cells subjected to SR (by 20+/-8%, 95+/-32% and 35+/-9%, respectively, at 100 U/ml). The effects of thrombin were associated to increased cytosolic Ca2+ overload, mimicked by 100 microM PAR-1 agonist peptide SFLLRNPNDKYEPF, and reversed by the direct thrombin inhibitor lepirudin (IC50=1.3+/-0.2 microg/ml).

The presence of thrombin during simulated ischemia-reperfusion increases cardiomyocyte cell death by a mechanism that involves activation of PAR-1 receptors and can be prevented by the direct thrombin inhibitor lepirudin [brand name Refludan].
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