To cite this article: Nylander S, Femia EA, Scavone M, Berntsson P, Aszt ely A-K, Nelander K, L€ ofgren L, Nilsson RG, Cattaneo M. Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y 12 antagonism. J Thromb Haemost 2013; 11: 1867-76.Summary. Background: Ticagrelor, a P2Y 12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells. Objective: To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A 2A receptor. Methods: Collagen-induced PA was measured in WB or platelet-rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y 12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A 2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y 12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared. Results: For PA in WB, adenosine contributed to drug-induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P < 0.01). For PA in PRP (no adenosine uptake by erythrocytes), adenosine contributed to inhibition of PA in the presence/absence of all tested drugs. ZM241385 reversed the inhibition by adenosine in WB and PRP. Similar results were obtained with WB and PRP from P2Y 12 -deficient patients. Adenosine (7.1 lmol L -1 ) added to WB, was detectable for 0.5 min in the presence of vehicle or PAM, for 3-6 min in the presence of ticagrelor, and for > 60 min in the presence of dipyridamole. Conclusion: This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.

Glycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from ␤ -oxidation and toward glycerolipid synthesis. Adenoviralmediated overexpression of murine mtGPAT in primary cultures of rat hepatocytes increased mtGPAT activity 2.7-fold with no compensatory effect on microsomal GPAT activity. MtGPAT overexpression resulted in a dramatic 80% reduction in fatty acid oxidation and a significant increase in hepatic diacylglycerol and phospholipid biosynthesis. Following lipid loading of the cells, intracellular triacylglycerol biosynthesis was also induced by mtGPAT overexpression. Changing an invariant aspartic acid residue to a glycine [D235G] in mtGPAT resulted in an inactive enzyme, which helps define the active site required for mammalian mtGPAT function. To determine if obesity increases hepatic mtGPAT activity, two models of rodent obesity were examined and shown to have Ͼ 2-fold increased enzyme activity.Overall, these results support the concept that increased hepatic mtGPAT activity associated with obesity positively contributes to lipid disorders by reducing oxidative processes and promoting de novo glycerolipid synthesis. -Lindén, D., L. William-Olsson, M. Rhedin, A-K. Asztély, J. C. Clapham, and S. Schreyer. Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis.

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