Gö 6983 Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion

Peterman, Ellen E.; Taormina, Philip; Harvey, Margaret; Young, Lindon H.

doi:10.1097/00005344-200405000-00006

Cited by 31 publications

(49 citation statements)

References 35 publications

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“…The isolated hearts were perfused via an aortic cannula and immersed in a water-jacketed reservoir containing 160 ml of Krebs' Hensleit buffer (KHB; in mmol/l: 17.0 dextrose, 120.0 NaCl, 25.0 NaHCO 3 , 2.5 CaCl 2 , 0.5 EDTA, 5.9 KCl, and 1.2 MgCl 2 ) maintained at 37°C and equilibrated with 95% O 2 -5% CO 2 to maintain a pH of 7.3-7.4. Perfusion pressure was maintained at 80 mmHg as previously described [36].…”

Section: Global Cardiac Ischemiamentioning

confidence: 99%

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

Blakeman¹,

Chen²,

Tolson³

et al. 2012

Am. J. Biomed. Sci.

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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 Am.

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Section: Global Cardiac Ischemiamentioning

confidence: 99%

“…[36]. At the end of the experiment, the infarct area was visualized by treatment with 1% 2,3,5-triphenyltetrazolium chloride (TTC).…”

Section: Global Cardiac Ischemiamentioning

confidence: 99%

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

Blakeman¹,

Chen²,

Tolson³

et al. 2012

Am. J. Biomed. Sci.

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“…It is known that coronary flow in the ex vivo isolated perfused rat heart model can have a wide variation of postreperfusion coronary flow (i.e. 7 to 14 ml/min) and this variable is independent of post-reperfused cardiac function within the 7-14 ml/min range among all MI/R study groups [7].…”

Section: Resultsmentioning

confidence: 99%

Comparison of the Effects of Myristoylated and Transactivating Peptide (TAT) Conjugated Mitochondrial Fission Peptide Inhibitor (P110) in Myocardial Ischemia/Reperfusion (I/R) Injury

Benjamin¹,

Vu²,

Lipscombe³

et al. 2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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“…As shown in Fig. 6, the pan-PKC inhibitors GF 109203X and Gö 6983, used at concentrations that fully block both conventional and novel PKC isoforms [35,36], suppressed the repressing effects of PMA towards OATP1B1, OATP2B1, NTCP and OCT1 mRNAs in HepaRG cells, without altering basal mRNA expression of these transporters; they also prevented the induction of OATP1B3 mRNAs.…”

Section: Involvement Of Pkcs In Pma-mediated Drug Transporter Regulationmentioning

confidence: 99%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-1 or the HNF4 inhibitor BI6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.

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Gö 6983 Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion

Cited by 31 publications

References 35 publications

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

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

Comparison of the Effects of Myristoylated and Transactivating Peptide (TAT) Conjugated Mitochondrial Fission Peptide Inhibitor (P110) in Myocardial Ischemia/Reperfusion (I/R) Injury

Protein kinase C-dependent regulation of human hepatic drug transporter expression

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