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Epoxyeicosatrienoic acids (EETs) protect cardiovascular cells from apoptosis mediated by caspase 3‐dependent pathways
Author(s) -
Dhanasekaran Anuradha,
Gruenloh Stephanie,
Jacobs Elizabeth,
Medhora Meetha
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a123-b
Subject(s) - apoptosis , epoxyeicosatrienoic acid , annexin , arachidonic acid , pharmacology , caspase 3 , caspase , cytochrome c , myocyte , chemistry , medicine , microbiology and biotechnology , biology , programmed cell death , biochemistry , enzyme
Apoptosis has recently been implicated in several cardiac diseases such as ischemia, myocardial infarction, hypertension, myocarditis and heart failure. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 derivatives of the free fatty acid, arachidonic acid, which mediate a number of important vascular functions. We have identified three EET regioisomers (14,15‐, 11,12‐ and 8,9‐EETs) that protect cultured human endothelial cells as well as rodent cardiomyocytes from apoptosis. Apoptosis was induced in cultured human lung microvascular (HLMVEC) and human coronary artery endothelial cells (HCAEC) by treatment with the potent apoptotic agent anti‐Fas antibody (100 ng/ml), or by deprivation of growth factors. Pretreatment of these cells with 3 of 4 regiosiomers of EETs (14,15‐, 11,12‐, 8,9‐ but not 5,6‐EET (300 nM each)) attenuated Fas‐induced apoptosis as evaluated by two different methods, an early Annexin V binding assay and a late Caspase ‐3 activity assay. These 3 EETs also inhibited apoptosis induced by hypoxia/reperfusion in cultured neonatal myocytes as well as the immortalized cardiomyocyte cell line, HL‐1. Pretreatment of cardiomyocytes with nanomolar concentrations of 14,15‐, 11,12‐ and 8,9‐ decreased annexin V binding as well as caspase‐3 activity (as assayed by immunofluoresence, spectrofluorimetry and immunoblotting). Our results identify a new role for EETs in protecting cardiac cells from apoptosis, making them ideal candidates for novel therapeutic intervention for mitigation and treatment of cardiovascular insults and injuries. This work is supported by NIH/NHLBI 69996, 68627 and 49294.