Triacsin C, a Fatty Acyl CoA Synthetase Inhibitor, Improves Cardiac Performance Following Global Ischemia

Lindon H. Young², Margaret T. Weis^1*

¹Department of Biomedical Sciences, Vascular Drug Research Center, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas, USA

²Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA

Corresponding Author:

Margaret T. Weis, Ph.D.

Department of Biomedical Sciences

School of Pharmacy

Texas Tech University Health Sciences Center

1300 Coulter Drive, Room 400

Amarillo, Texas 79106

USA

806.356.4015, ext. 281 (voice)

806.356.4643 (fax)

Margaret.weis@ttuhsc.edu

Nina Blakeman and Qian Chen both contributed equal effort and are co-first authors for this manuscript

Abstract

       The role of fatty acyl CoA synthetase (FACS) in ischemia/reperfusion (I/R) injury has not been well established. Our earlier studies showed that triacsin C, a selective FACS inhibitor, decreases endothelial nitric oxide synthase (eNOS) palmitoylation and increases nitric oxide (NO) in cultured human coronary endothelial cells. In the present study, we tested the hypothesis that triacsin C would reduce infarct size and improve post-reperfusion cardiac function by increasing vascular NO. In isolated rat hearts, triacsin C, given during the first 5 minutes of reperfusion, significantly reduced infarct size and attenuated cardiac dysfunction during reperfusion. N^G-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 50 µM) completely abolished the protective effects of triacsin C. In the ischemic hind limb model, triacsin C significantly increased intravascular NO concentration during reperfusion, an effect that was blocked by L-NAME or S-methyl-L-thiocitrulline (SMTC, a selective neuronal NOS inhibitor), but not by 1400W (a highly selective iNOS inhibitor). Lastly, triacsin C significantly reduced L-NAME induced leukocyte rolling, adhesion, and transmigration in rat mesenteric circulation, as measured by intravital microscopy. In summary, this study provides novel evidence showing that triacsin C reduces myocardial infarct size, attenuates loss of post-reperfusion cardiac function, increases intravascular NO concentration and inhibits leukocyte recruitment. These pharmacologic properties suggest that triacsin C may be useful as an adjunct to standard thrombolytic/anti-platelet pharmacotherapy of myocardial infarction.

Keywords: fatty acyl CoA synthetase, triacsin C, myocardial ischemia/reperfusion, cardiac function, infarct size, nitric oxide, inflammation.

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