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Novel fatty acyl CoA synthetase (FACS) inhibitors – new tools to study ischemia/reperfusion (I/R) injury
Author(s) -
Blakeman Nina Ruth,
Prior Allan M,
Pokhrel Laxman,
Hua Duy H,
Weis Margaret T
Publication year - 2013
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.27.1_supplement.1130.3
Subject(s) - enos , chemistry , nitric oxide , enzyme , biochemistry , nitrite , nitric oxide synthase , organic chemistry , nitrate
Human coronary endothelial cells treated with triacsin C, a fatty acyl CoA synthetase (FACS) inhibitor, show elevated endothelial nitric oxide synthase (eNOS) activity but not elevated eNOS protein. In a model of cardiac ischemia/reperfusion (I/R) injury, triacsin C both reduced infarct volume and improved contractility (Blakeman et al, 2012). These findings strongly suggest that one or more FACS isoforms mediate I/R injury by increasing eNOS activity, and have led us to explore a series of triacsin C analogs. Compounds 1e and 1b(a) were synthesized as described (Kim et al., 2012). In solubilized bEND5 cells, palmitoyl CoA synthesis was inhibited with IC 50 values of 242 nM (triacsin C), 5.6 μM (compound 1e), and 168 μM (compound 1b(a)). Incorporation of [ 14 C]palmitate in bEND3 cells was measured and results shown below.Control 1.5 μM Triacsin C 15 μM 1e 15 μM 1b(a)Lipid 1470±68 pmol 631±65 pmol * 617±35 pmol * 1380±83 pmol Aqueous 32.5±3.7 pmol 2.56±0.3 pmol * 6.15±1.1 pmol * 38.3±9.3 pmolBoth triacsin C and compound 1e, but not compound 1b(a), significantly elevated 24‐hour media nitrite accumulation (128 ± 3.23% of control and 110 ± 4.16 % of control, respectively). These results suggest that increased eNOS activity is the consequence of FACS inhibition and that both triacsin C and compound 1e inhibit the incorporation of [ 14 C]palmitate into cellular lipids to a similar extent..